Benzylidene-1,3-dihydro-indol-2-one derivatives a receptor tyrosine kinase inhibitors, particularly of Raf kinases

ABSTRACT

Compounds of general formula (I) wherein: R 1  is H or optionally joined with R 2  to form a fused ring selected from the group consisting of five to ten membered aryl, heteroaryl or heterocyclyl rings, R 2  and R 3  are independently H, HET, aryl, C 1-12  aliphatic, CN, NO 2 , halogen, R 10 , —OR 10 , —SR 10 , —S(O)R 10 , —SO 2 R 10 , —NR 10 R 11 , —NR 11 R 12 , —NR 12 COR 11 , —NR 12 CO 2 R 11 , —NR 12 CONR 11 R 12 , —NO 12 SO 2 R 11 , —NR 12 C(NR  12 )NHR 11 , —COR 11 , —CO 2 R 11 , —CONR 12 R 11 , —SO 2 NR 12 R 11 , —OCONR 12 R 11 , C(NR 12 )NR 12 R 11 , R 6  and R 7  are independently halogen, CN, NO 2 , —CONR 10 R 11 , —SO 2 NR 10 R 11 , —NR 10 R 11 , or —OR 11 , where R 10  and R 11  are as defined below; R 8  is OH, NHSO 2 R 12  or NHCOCF 3 ; and their use in therapy, especially in the treatment of disorders mediated by cRaf1 kinase.

FIELD OF THE INVENTION

The present invention provides novel compounds, novel compositions,methods of their use and methods of their manufacture, such compoundsgenerally pharmacologically useful as agents in those disease statesalleviated by the alteration of mitogen activated signalling pathways ingeneral, and in particular the inhibition or antagonism of proteinkinases, which pathologically involve aberrant cellular proliferation,such disease states including tumor growth. The aforementionedpharmacologic activities are useful in the treatment of mammals. Inparticular, the invention relates to benzylidene oxindole derivativeswhich exhibit cRaf-1 kinase inhibition for the treatment of disordersrelated to cell proliferation.

More specifically, the compounds of the present invention can be used inthe treatment of certain forms of cancer, can be used to provideadditive or synergistic effects with certain existing cancerchemotherapies, and/or used to restore effectiveness of certain existingcancer chemotherapies and radiation. At the present time, there is aneed in the areas of diseases characterized by cell proliferation forsuch therapeutic agents.

BACKGROUND OF THE INVENTION

Cancer results from the deregulation of the normal processes thatcontrol cell division, differentiation and apoptotic cell death. Proteinkinases play a critical role in this regulatory process. A partialnon-limiting list of such kinases includes ab1, ATK, bcr-ab1, Blk, Brk,Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK,EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4,FGFR5, Fgr, FLK4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR,Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie₁, tie₂, TRK, Yes andZap70. In mammalian biology, such protein kinases comprise mitogenactivated protein kinase (MAPK) signalling pathways. MAPK signallingpathways are inappropriately activated by a variety of commondisease-associated mechanisms such as mutation of ras genes andderegulation of growth factor receptors (Magnuson et al, Seminars inCancer Biology; 1994 (5), 247-252). Therefore the inhibition of proteinkinases is an object of the present invention.

Additionally, protein kinases have been implicated as targets in centralnervous system disorders (such as Alzheimer's), inflammatory disorders(such as psoriasis), bone diseases (such as osteoporosis),atheroscleroses, restenosis, thrombosis, metabolic disorders (such asdiabetes) and infectious diseases (such as viral and fungal infections).

One of the most commonly studied pathways involving kinase regulation iscellular signalling from receptors at the cell surface to the nucleus(Crews and Erikson, 1993). One example of this pathway includes acascade of kinases in which members of the Growth Factor receptorTyrosine Kinases (such as EGF-R, PDGF-R, VEGF-R, IGF1-R, the Insulinreceptor), deliver signals through phosphorylation to other kinases suchas Src Tyrosine kinase, and the Raf, Mek and Erk serine/threonine kinasefamilies (Crews and Erikson, 1993; Ihle et al., 1994). Each of thesekinases is represented by several family members (Pelech and Sanghera,1992) which play related, but functionally distinct roles. The loss ofregulation of the growth factor signalling pathway is a frequentoccurrence in cancer as well as other disease states.

The signals mediated by kinases have also been shown to control growth,death and differentiation in the cell by regulating the processes of thecell cycle (Massague and Roberts, 1995). Progression through theeukaryotic cell cycle is controlled by a family of kinases called cyclindependent kinases (CDKs) (Myerson et al., 1992). The regulation of CDKactivation is complex, but requires the association of the CDK with amember of the cyclin family of regulatory subunits (Draetta, 1993;Murray and Kirschner, 1989; Solomon et al., 1992). A further level ofregulation occurs through both activating and inactivatingphosphorylations of the CDK subunit (Draetta, 1993; Ducommun et al.,1991; Gautier et al., 1989; Gould and Nurse, 1989; Krek and Nigg, 1991;Murray and Kirschner, 1989; Solomon et al., 1992; Solomon et al., 1990).The coordinate activation and inactivation of different cyclin/CDKcomplexes is necessary for normal progression through the cell cycle(Pines, 1993; Sherr, 1993). Both the critical G1-S and G2-M transitionsare controlled by the activation of different cyclin/CDK activities. InG1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate theonset of S-phase (Matsushime et al., 1994; Ohtsubo and Roberts, 1993;Quelle et al., 1993; Resnitzky et al., 1994). Progression throughS-phase requires the activity of cyclin A/CDK2 (Girard et al., 1991;Pagano et al., 1992; Rosenblatt et al., 1992; Walker and Maller, 1991;Zindy et al., 1992) whereas the activation of cyclin A/cdc2 (CDK1) andcyclin B/cdc2 are required for the onset of metaphase (Draetta, 1993;Girard et al., 1991; Murray and Kirschner, 1989; Pagano et al., 1992;Rosenblatt et al., 1992; Solomon et al., 1992; Walker and Maller, 1991;Zindy et al., 1992). It is not surprising, therefore, that the loss ofcontrol of CDK regulation is a frequent event in hyperproliferativediseases and cancer. (Hunter and Pines, 1994; Lees, 1995; Pines, 1992)

The kinase cRaf1 regulates cellular proliferation in two ways. Theenzyme positively regulates cell division through the Raf/MEK/ERKprotein kinase cascade. This activation is the result of cRaf1 catalyzedphosphorylation of the protein kinase, MEK1. MEK1 phosphorylates andactivates the protein kinase ERK. ERK phosphorylates and regulatestranscription factors required for cell division (Avruch et al, TIBS;1994 (19) 279-283). cRaf1 negatively regulates cell death by modulationof the activity of Bcl-2, a critical regulator of apoptosis. Thisregulation involves direct phosphorylation of Bcl-2 family members(Gajewski and Thompson, Cell: 1996 (87) 619-628). Both of these aspectsof cRaf1 mediated regulation of cellular proliferation require thekinase activity of cRaf1.

cRaf1 is deregulated by events that are common in human cancer. Forexample ras genes are mutated with the following frequencies in thefollowing representative primary human tumors: lung (adenocarcinoma),30%; colon (adenocarcinoma), 50%; pancreatic carcinoma, 90%; seminoma,40%; thyroid, 50% (McCormick, Ras oncogenes in Oncogenes and themolecular origins of cancer: 1989, 125-146). cRaf1 is also activated byderegulation of tyrosine kinases including, cSrc, ErbB2, EGFR, andbcr/abl. These events are associated with breast, colon and lungcarcinomas and chronic myelogenous leukemia (Fearon, Genetic lesions inhuman cancer, in Molecular oncology; 1996, 143-178). In addition, Rafanti-sense literature teaches that the reduction of Raf protein levelscorrelates with a reduction in tumor growth rate in in vivo tumor mousemodels. Inhibitors of the kinase activity of cRaf1 should thereforeprovide effective treatment for a wide variety of common human cancers.

Inhibitors of kinases involved in mediating or maintaining these diseasestates represent novel therapies for these disorders. Examples of suchkinases include, but are not limited to: (1) inhibition of Src(Brickell, 1992; Courtneidge, 1994), raf (Powis, 1994) and thecyclin-dependent kinases (CDKs) 1, 2 and 4 in cancer (Hunter and Pines,1994; Lees, 1995; Pines, 1992), (2) inhibition of CDK2 or PDGF-R kinasein restenosis (Buchdunger et al., 1995), (3) inhibition of CDK5 and GSK3kinases in Alzheimers (Aplin et al., 1996; Hosoi et al., 1995), (4)inhibition of c-Src kinase in osteoporosis (Tanaka et al., 1996), (5)inhibition of GSK-3 kinase in type-2 diabetes (Borthwick et al., 1995);(6) inhibition of the p38 kinase in inflammation (Badger et al., 1996);(7) inhibition of VEGF-R 1-3 and TIE-1 and -2 kinases in angiogenesis(Shawver et al., 1997); (8) inhibition of UL97 kinase in viralinfections (He et al., 1997); (9) inhibition of CSF-1R kinase in boneand hematopoetic diseases (Myers et al., 1997), and (10) inhibition ofLck kinase in autoimmune diseases and transplant rejection (Myers etal., 1997)

The present invention relates to certain benzylidene oxindolederivatives which not only have anti-cancer properties but also areselective and potent inhibitors of the serine/threonine kinase cRaf1thereby allowing selective reduction or elimination of particulardisease tissues. Some of the compounds of the present invention mayselectively inhibit another therapeutically relevent kinase.

It is an object of the present invention to provide potent specific,orally, intravenously, or subcutaneously active small moleculeinhibitors of the signal transduction activity of Raf kinases for thetreatment of human malignancies, for example, one or more of breast,stomach, ovary, colon, lung, brain, larynx, lymphatic system,genitourinary tract (including bladder and prostate), ovarian, gastric,bone, or pancreatic tumors, preferably those which signal throughcRaf-1, using the compounds of the present invention, methods of theiradministration, methods of their formulation, and methods of theirsynthesis.

The compounds of the present invention are additionally useful in thetreatment of one or more diseases afflicting mammals which arecharacterized by cellular proliferation in the areas of blood vesselproliferative disorders, fibrotic disorders, mesangial cellproliferative disorders and metabolic diseases. Blood vesselproliferative disorders include arthritis and restenosis. Fibroticdisorders include hepatic cirrhosis and atherosclerosis. Mesangial cellproliferative disorders include glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, organ transplant rejection and glomerulopathies. Metabolicdisorders include psoriasis, diabetes mellitus, chronic wound healing,inflammation and neurodegenerative diseases.

SUMMARY OF THE INVENTION

In summary, the invention includes a family of compounds having thegeneral structural formula (I):

wherein:

R¹ is H or optionally joined with R² to form a fused ring selected fromthe group consisting of five to ten membered aryl, heteroaryl orheterocyclyl rings, said heteroaryl or said heterocyclyl rings havingone to three heteroatoms where zero to three of said heteroatoms are Nand zero to 1 of said heteroatoms are O or S and where said fused ringis optionally substituted by one to three of R⁹, where R² and R⁹ are asdefined below;

R² and R³ are independently H, HET, aryl, C₁₋₂ aliphatic, CN, NO₂,halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —NR¹¹R¹²,—NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹,—COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹where said C₁₋₁₂ aliphatic optionally bears one or two insertions of oneto two groups selected from C(O), O, S, S(O), SO₂ or NR¹²; with saidHET, aryl or C₁₋₁₂ aliphatic being optionally substituted by one tothree of R¹⁰; and where R² is optionally joined with R³ to form a fusedring selected from the group consisting of five to ten membered aryl,heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclylrings having zero to three heteroatoms where zero to three of saidheteroatoms are N and zero to one of said heteroatoms are O or S andwhere said fused ring is optionally substituted by one to three of R⁹,where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

R⁴ is H, halogen, NO₂ or CN;

R⁵ is H or C₁₋₁₂ aliphatic optionally substituted by one to three ofhalo, hydroxyl, heteroaryl, or aryl;

R⁶ and R⁷ are independently halogen, CN, NO₂, —CONR¹⁰R¹¹, —SO₂NR¹⁰R¹¹,—NR¹⁰R¹¹, or —OR¹¹, where R¹⁰ and R¹¹ are as defined below;

R⁸ is OH, NHSO₂R¹² or NHCOCF₃;

R⁹ is each independently halogen, C₁₋₁₂ aliphatic, CN, —NO₂, R¹⁰, —OR¹¹,—SR¹¹, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —N¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹,—NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —CO₂R¹¹, —CONR¹²R¹¹,—SO₂NR¹²R¹¹, —OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² areas defined below;

R¹⁰ is each independently H, halogen, C₁₋₁₂ aliphatic, aryl or HET,where said C₁₋₁₂ aliphatic optionally bears an inserted one to twogroups selected from O, S, S(O), SO₂ or NR¹², where said C₁₋₁₂aliphatic, aryl or HET is optionally substituted by one to three ofhalo, another HET, aryl, CN, —SR¹², —OR¹², —N(R¹²)₂, —S(O)R¹², —SO₂R₁₂,—SO₂N(R¹²)₂, —NR¹²COR¹², —NR¹²CO₂R¹², —NR¹²CON(R¹²)₂, —NR¹²(NR¹²)NHR¹²,—CO₂R¹², —CON(R¹²)₂, —NR¹²SO₂R¹², —OCON(R¹²)₂, where HET and R¹² are asdefined below;

R¹¹ is H or R¹⁰;

R¹² is H, C₁₋₁₂ aliphatic or HET, said C₁₋₁₂ aliphatic optionallysubstituted by one to three of halogen or OH where HET is as definedbelow; and

HET is a five to ten—membered saturated or unsaturated heterocyclic ringselected from the group consisting of benzofuran, benzoxazole, dioxin,dioxane, dioxolane, dithiane, dithiazine, dithiazoie, dithiolane, furan,imidazole, indole, indazole, morpholine, oxazole, oxadiazole,oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine,piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole,pyrrolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine,tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine,thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, andtriazole;

and the pharmaceutically acceptable salts, biohydrolyzable esters,biohydolyzable amides, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, solvates, hydrates, affinityreagents or prodrugs of (I) as defined above.

A preferred group of compounds of the present invention are those of thegeneral formula (I)

wherein R¹ is H or optionally joined with R² to form a fused ringselected from the group as defined for HET below, and where said fusedring is optionally substituted by one to three of R⁹, where R² and R⁹are as defined below;

R² and R³ are independently H, HET, aryl, C₁₋₆ aliphatic, CN, NO₂,halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —NR¹¹R¹²,—NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹,—COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹where said C₁₋₆ aliphatic optionally bears one or two insertions of oneto two groups selected from C(O), O, S, S(O), SO₂ or NR¹²; with saidHET, aryl or C₁₋₆ aliphatic being optionally substituted by one to threeof R¹⁰; and where R² is optionally joined with R³ to form a fused ringselected from the group as defined below and where said fused ring isoptionally substituted by one to three of R⁹, where HET, R⁹, R¹⁰, R¹¹and R¹² are as defined below;

R⁴ is H, halogen, NO₂ or CN;

R⁵ is H or C₁₋₆ aliphatic optionally substituted by one to three ofhalo, OH, or aryl;

R⁶ and R⁷ are independently halogen, CN, NO₂, —CONR¹⁰R¹¹, —SO₂NR¹⁰R¹¹,—NR¹⁰R¹¹, or —OR¹¹, where R¹⁰ and R¹¹ are as defined below;

R⁸ is OH, NHSO₂R¹² or NHCOCF₃;

R⁹ is each independently halo, C₁₋₆ aliphatic, CN, —NO₂, R¹⁰, —OR¹¹,—SR¹¹, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —N¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹,—NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —CO₂R¹¹, —CONR¹²R¹¹,—SO₂NR¹²R¹¹, —OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² areas defined below;

R¹⁰ is each independently H, halogen, C₁₋₆ aliphatic, aryl or HET, wheresaid C₁₋₆ aliphatic optionally bears an inserted one to two groupsselected from O, S, S(O), SO₂ or NR¹², where said C₁₋₆ aliphatic, arylor HET is optionally substituted by one to three of halo, another HET,aryl, CN, —SR¹², —OR¹², —N(R¹²)₂, —S(O)R¹², —SO₂R¹², —SO₂N(R¹²)₂,—NR¹²COR¹², —NR¹²CO₂R¹², —NR¹²CON(R¹²)₂, —NR(NR¹²)NHR¹², —CO₂R¹²,—CON(R¹²)₂, —NR¹²SO₂R¹², —OCON(R¹²)₂, where HET and R¹² are as definedbelow;

R¹¹ is H or R¹⁰;

R¹² is H, C₁₋₆ aliphatic or HET, said C₁₋₆ aliphatic optionallysubstituted by one to three of halogen or OH where HET is as definedbelow; and

HET is a five to ten—membered saturated or unsaturated heterocyclic ringselected from the group consisting of benzofuran, benzoxazole, dioxin,dioxane dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, indole, indazole, morpholine, oxazole, oxadiazole,oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine,piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole,pyrrolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine,tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine,thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, andtriazole;

and the pharmaceutically acceptable salts, biohydrolyzable esters,biohydolyzable amides, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, solvates, hydrates, affinityreagents or prodrugs of (I) as defined above.

A highly preferred group of compounds of the present invention are thoseof the general formula (I)

wherein R¹ is H or optionally joined with R² to form a fused ringselected from the group consisting of fused pyridine, fused triazole,fused thiazole or fused amino-substituted thiazole;

R² and R³ are independently H, HET, aryl, C₁₋₆ aliphatic, —R¹²NH₂,—R¹²-halogen, CN, NO₂, halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰,—NR¹⁰R¹¹, —NR¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹²,—NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —COR¹¹, —COR¹¹NR¹²R¹¹—CO₂R¹¹,—CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹, —C(NH)R¹¹, —C(NR¹²)NR¹²R¹¹ wheresaid C₁₋₆ aliphatic optionally bears an insertion of a C(O) group; withsaid HET, aryl or C₁₋₆ aliphatic being optionally substituted by one tothree of R¹⁰; and where R² is optionally joined with R³ to form a fusedring selected from the group as defined for HET below and where saidfused ring is optionally substituted by one to three of R⁹, where HET,R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

R⁴ is H, halogen, NO₂ or CN;

R⁵ is H or C₁₋₆ aliphatic optionally substituted by one to three ofhalogen, OH, or aryl;

R⁶ and R⁷ are independently halogen, CN, NO₂, —CONR¹⁰R¹¹, —SO₂NR¹⁰R¹¹,—NR¹⁰R¹¹, or —OR¹¹, where R¹⁰ and R¹¹ are as defined below;

R⁸ is OH, NHSO₂R¹² or NHCOCF₃;

R⁹ is each independently halo, C₁₋₆ aliphatic, CN, —NO₂, R¹⁰, —OR¹¹,—SR¹¹, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —N¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹,—NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —CO₂R¹¹, —CONR¹²R¹¹,—SO₂NR¹²R¹¹, —OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² areas defined below;

R¹⁰ is each independently H, halogen, C₁₋₆ aliphatic, aryl or HET, wheresaid C₁₋₆ aliphatic optionally bears an inserted one to two groupsselected from O, S, S(O), SO₂ or NR¹², where said C₁₋₆ aliphatic, arylor HET is optionally substituted by one to three of halo, another HET,aryl, CN, NO₂—R¹², —SR¹², —OR¹², —N(R¹²)₂, —R¹²N(R¹²)₂—S(O)R¹², —SO₂R¹²,—SO₂N(R¹²)₂, —NR¹²COR¹², —NR¹²CO₂R¹², —NR¹²CON(R¹²)₂, —NR¹²(NR¹²)NHR¹²,—CO₂R¹², —CON(R¹²)₂, —NR¹²SO₂R¹², —OCON(R¹²)₂, or trifluoro, where HETand R¹² are as defined below;

R¹¹ is H or R¹⁰;

R¹² is H, C₁₋₆ aliphatic, NO₂, C₁₋₆ alkoxy, halogen, aryl or HET, saidC₁₋₆ aliphatic optionally substituted by one to three of halogen or OHwhere HET is as defined below;

HET is a five or six-membered saturated or unsaturated heteroaryl ringselected from the group consisting of dioxin, dioxane, dioxolane,dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole,imidazopyridinyl, morpholine, oxazole, oxadiazole, oxathiazole,oxathiazolidine, oxazine, oxiadiazine, piperazine, piperidine, pyran,pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine,tetrahydrofuran, tetrazine, thiophene, thiadiazine, thiadiazole,thiatriazole, thiazine, thiazole, thiomorpholine, thiopyran,thioxotriazine, triazine, and triazole;

and the pharmaceutically acceptable salts, biohydrolyzable esters,biohydolyzable amides, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, solvates, hydrates, affinityreagents or prodrugs of (I) as defined above.

Also highly preferred is a compound of formula (I) in which R¹ and R²additionally comprise a fused ring which is methyl substituted fusedpyridine.

A group of compounds that are preferred with respect to theirsubstituents at positions R⁶, R⁷ and R⁸ are compounds of the formula:

wherein:

R¹ is H or optionally joined with R² to form a fused ring selected fromthe group consisting of five to ten membered aryl, heteroaryl orheterocyclyl rings, said heteroaryl or said heterocyclyl rings havingone to three heteroatoms where zero to three of said heteroatoms are Nand zero to 1 of said heteroatoms are O or S and where said fused ringis optionally substituted by one to three of R⁹, where R² and R⁹ are asdefined below;

R² and R³ are independently H, HET, aryl, C₁₋₁₂ aliphatic, CN, NO₂,halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —NR¹¹R¹²,—NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹,—COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹where said C₁₋₁₂ aliphatic optionally bears one or two insertions of oneto two groups selected from C(O), O, S, S(O), SO₂ or NR¹²; with saidHET, aryl or C₁₋₁₂ aliphatic being optionally substituted by one tothree of R¹⁰; and where R² is optionally joined with R³ to form a fusedring selected from the group consisting of five to ten membered aryl,heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclylrings having zero to three heteroatoms where zero to three of saidheteroatoms are N and zero to one of said heteroatoms are O or S andwhere said fused ring is optionally substituted by one to three of R⁹,where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

R⁴ is H, halogen, NO₂ or CN;

R⁵ is H or C₁₋₁₂ aliphatic optionally substituted by one to three ofhalo, hydroxyl, or aryl;

R⁶ and R⁷are halogen;

R⁸is OH;

R⁹ is each independently halogen, C₁₋₁₂ aliphatic, CN, —NO₂, R¹⁰, —OR¹¹,—SR¹¹, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —N¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹,—NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —CO₂R¹¹, —CONR¹²R¹¹,—SO₂NR¹²R¹¹, —OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² areas defined below;

R¹⁰ is each independently H, halogen, C₁₋₁₂ aliphatic, aryl or HET,where said C₁₋₁₂ aliphatic optionally bears an inserted one to twogroups selected from O, S, S(O), SO₂ or NR¹², where said C₁₋₁₂aliphatic, aryl or HET is optionally substituted by one to three ofhalo, another HET, aryl, CN, —SR¹², —OR¹², —N(R¹²)₂, —S(O)R¹², —SO₂R¹²,—SO₂N(R¹²)₂, —NR¹²COR¹², —NR¹²CO₂R¹², —NR¹²CON(R¹²)₂, —NR¹²(NR¹²)NHR¹²,—CO₂R¹², —CON(R¹²)₂, —NR¹²SO₂R¹², —OCON(R¹²)₂, where HET and R¹² are asdefined below;

R¹¹ is H or R¹⁰;

R¹² is H, C₁₋₁₂ aliphatic or HET, said C₁₋₁₂ aliphatic optionallysubstituted by one to three of halogen or OH where HET is as definedbelow; and

HET is a five to ten-membered saturated or unsaturated heterocyclic ringselected from the group consisting of benzofuran, benzoxazole, dioxin,dioxane dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, indole, indazole, morpholine, oxazole, oxadiazole,oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine,piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole,pyrrolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine,tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine,thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, andtriazole;

and the pharmaceutically acceptable salts, biohydrolyzable esters,biohydolyzable amides, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, solvates, hydrates, affinityreagents or prodrugs of (I) as defined above.

Another group of compounds that are preferred with respect to theirsubstituents at positions R⁶ R⁷ and R⁸ are compounds of the formula:

wherein:

R¹ is H or optionally joined with R² to form a fused ring selected fromthe group consisting of five to ten membered aryl, heteroaryl orheterocyclyl rings, said heteroaryl or said heterocyclyl rings havingone to three heteroatoms where zero to three of said heteroatoms are Nand zero to 1 of said heteroatoms are O or S and where said fused ringis optionally substituted by one to three of R⁹, where R² and R⁹ are asdefined below;

R² and R³ are independently H, HET, aryl, C₁₋₁₂ aliphatic, CN, NO₂,halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —NR¹¹R¹²,—NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹,—COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹where said C₁₋₁₂ aliphatic optionally bears one or two insertions of oneto two groups selected from C(O), O, S, S(O), SO₂ or NR¹²; with saidHET, aryl or C₁₋₁₂ aliphatic being optionally substituted by one tothree of R¹⁰; and where R²is optionally joined with R³ to form a fusedring selected from the group consisting of five to ten membered aryl,heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclylrings having zero to three heteroatoms where zero to three of saidheteroatoms are N and zero to one of said heteroatoms are O or S andwhere said fused ring is optionally substituted by one to three of R⁹,where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

R⁴ is H, halogen, NO₂ or CN;

R⁵ is H or C₁₋₁₂ aliphatic optionally substituted by one to three ofhalo, hydroxyl, or aryl;

R⁶ and R⁷ are independently bromo or chloro;

R⁸ is OH;

R⁹ is each independently halogen, C₁₋₁₂ aliphatic, CN, —NO₂, R¹⁰, —OR¹¹,—SR¹¹, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —N¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹,—NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —CO₂R¹¹, —CONR¹²R¹¹,—SO₂NR¹²R¹¹, —OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² areas defined below;

R¹⁰ is each independently H, halogen, C₁₋₁₂ aliphatic, aryl or HET,where said C₁₋₁₂ aliphatic optionally bears an inserted one to twogroups selected from O, S, S(O), SO₂ or NR¹², where said C₁₋₁₂aliphatic, aryl or HET is optionally substituted by one to three ofhalo, another HET, aryl, CN, —SR¹², —OR¹², —N(R¹²)₂, —S(O)R¹², —SO₂R¹²,—SO₂N(R¹²)₂, —NR¹²COR¹², —NR¹²CO₂R¹², —NR¹²CON(R¹²)₂, —NR¹²(NR¹²)NHR¹²,—CO₂R¹², —CON(R¹²)₂, —NR¹²SO₂R¹², —OCON(R¹²)₂, where HET and R¹² are asdefined below;

R¹¹ is H or R¹⁰;

R¹² is H, C₁₋₁₂ aliphatic or HET, said C₁₋₁₂ aliphatic optionallysubstituted by one to three of halogen or OH where HET is as definedbelow; and

HET is a five to ten-membered saturated or unsaturated heterocyclic ringselected from the group consisting of benzofuran, benzoxazole, dioxin,dioxane dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,imidazole, indole, indazole, morpholine, oxazole, oxadiazole,oxathiazole, oxathiazolidine, oxazine, oxiadiazine, piperazine,piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole,pyrrolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine,tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine,thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, andtriazole;

and the pharmaceutically acceptable salts, biohydrolyzable esters,biohydolyzable amides, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, solvates, hydrates, affinityreagents or prodrugs of (I) as defined above.

Yet another group of compounds that are preferred with respect to theirsubstituents at positions R⁶, R⁷ and R⁸ are compounds of the formula:

wherein

R¹ is H or optionally joined with R² to form a fused ring selected fromthe group consisting of five to six membered heteroaryl rings, saidheteroaryl ring having one to two heteroatoms where zero to two of saidheteroatoms are N and zero to two of said heteroatoms are O or S andwhere said fused ring is optionally substituted by one to three of R⁹,where R² and R⁹ are as defined below;

R² and R³ are independently H, HET, phenyl, C₁₋₆ aliphatic, —NR¹⁰OR¹¹,—COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, with said HET, phenyl or C₁₋₆aliphatic being optionally substituted by R¹⁰; and where R² isoptionally joined with R³ to form a fused five membered heterocyclylring, said heterocyclyl ring having zero to 1 heteroatoms where saidheteroatom is N and zero to 1 heteroatoms where said heteroatoms are Oor S and where said fused ring is optionally substituted by R⁹, whereHET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;

R⁴ is H;

R⁵ is H;

R⁶ and R⁷ are independently bromo or chloro;

R⁸ is OH;

R⁹ is H, C₁₋₆ aliphatic, or —COR¹⁰, where R¹⁰ is as defined below;

R¹⁰ is H, C₁₋₆ aliphatic or amino;

R¹¹ is H, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic, phenyl, phenyl-C₁₋₆aliphatic or HET;

R¹² is H, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic or (R¹¹)₂N—C₁₋₆aliphatic; and

HET is a heterocyclic ring selected from the group consisting ofoxazole, pyridine, tetrazole and thiazole;

and the pharmaceutically acceptable salts, biohydrolyzable esters,biohydolyzable amides, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, solvates, hydrates, affinityreagents or prodrugs of (I) as defined above.

Still another group of compounds that are preferred with respect totheir substituents at positions R⁶, R⁷ and R⁸ are compounds of theformula:

wherein

R¹ is H;

R² and R³ are independently H, HET, phenyl, C₁₋₆ aliphatic, cyano,halogen, —COR¹¹, or —CONR¹²R¹¹, with said HET, phenyl or C₁₋₆ aliphaticbeing optionally substituted by R¹⁰, where HET, R¹⁰, R¹¹ and R¹² are asdefined below;

R⁴ is H;

R⁵ is H;

R⁶ and R⁷ are independently bromo or chloro;

R⁸ is OH;

R¹⁰ is H, C₁₋₆ aliphatic, oxo or cyano;

R¹¹ is H, C₁₋₆ aliphatic, trihalo-C₁₋₆ aliphatic, phenyl ornitro-substituted phenyl;

R¹² is H, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic; and

HET is thiophene or pyridine;

and the pharmaceutically acceptable salts, biohydrolyzable esters,biohydolyzable amides, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, solvates, hydrates, affinityreagents or prodrugs of (I) as defined above.

Certain compounds of formula (I) above may exist in stereoisomeric forms(e.g. they may contain one or more asymmetric carbon atoms or mayexhibit cis-trans isomerism). The individual stereoisomers (enantiomersand diastereoisomers) and mixtures of these are included within thescope of the present invention. Likewise, it is understood thatcompounds of formula (I) may exist in tautomeric forms other than thatshown in the formula and these are also included within the scope of thepresent invention.

Due to the presence of a double bond, also included in the compounds ofthe invention are their respective pure E and Z geometric isomers aswell as mixtures of E and Z isomers.

E/Z Mixture

The invention as described and claimed does not set any limiting ratioson prevalence of Z to E isomers.

Thus, compound3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-pyrid-3-yl-1,3-dihydro-indol-2-one,compound number 138 in the tables below, is disclosed and claimed as theE geometric isomer thereof, the Z geometric isomer and a mixture of theE and Z geometric isomers thereof, but not limited by any givenratio(s).

Certain of the compounds as described will contain one or more chiralcarbons and will therefore be either dextrorotatory or levorotatory.Also included in the compounds of the invention are the respectivedextrorotatory or levorotatory pure preparations, and racemic mixturesthereof.

Salts of the compounds of the present invention may comprise acidaddition salts derived from a nitrogen on a substituent in the compoundof formula (I). The therapeutic activity resides in the moiety derivedfrom the compound of the invention as defined herein and the identity ofanother component is of less importance although for therapeutic andprophylactic purposes it is, preferably, pharmaceutically acceptable tothe patient.

Highly preferred biohydrolyzable carbamates comprise compounds offormula (i), wherein R⁸ is OH and said OH is conjugated with a carbamoylconjugate to yield a biohydrolyzable carbamate wherein said carbamoylconjugate is selected from the group consisting of diethylaminocarbonyl,N-(2-hydroxyethyl)aminocarbonyl, N,N,-bis(2-hydroxyethyl)aminocarbonyl,hydroxyethyloxyethylaminocarbonyl, 4-morpholinocarbonyl and4-methyl-1-piperazinylcarbonyl.

Highly preferred biohydrolyzable carbonates comprise compounds offormula (I), wherein R⁸ is OH and said OH is conjugated with a carbonateconjugate to yield a biohydrolyzable carbonate wherein said carbonylconjugate is selected from the group consisting ofphenylmethyloyxcarbonyl, ethyloxycarbonyl, isobutyloxycarbonyl, andpyridinemethyloxycarbonyl.

Highly preferred biohydrolyzable esters comprise compounds of formula(I), wherein R⁸ is OH and said OH is conjugated with an ester conjugateto yield a biohydrolyzable ester wherein said ester conjugate isselected from the group consisting of t-butylcarbonyloxymethyl.

The invention further includes a compound of formula (I) or one of itspharmaceutically acceptable salts, prodrugs, biohydrolyzable esters,amides, carbonates, amines, ureides or carbamates for use in thepreparation of a medicament for the treatment of disorders mediated byprotein kinase activity.

The invention further includes a compound of formula (I) or one of itspharmaceutically acceptable salts, prodrugs, biohydrolyzable esters,amides, carbonates, amines, ureides or carbamates for use in thepreparation of a medicament for the treatment of disorders mediated bydisorders caused by a mutated ras gene.

The invention further includes a compound of formula (I) or one of itspharmaceutically acceptable salts, prodrugs, biohydrolyzable esters,amides, carbonates, amines, ureides or carbamates for use in thepreparation of a medicament for the treatment of disorders mediated byan upregulated tyrosine kinase signalling pathway.

The invention further includes a compound of formula (I) or one of itspharmaceutically acceptable salts, prodrugs, biohydrolyzable esters,amides, carbonates, amines, ureides or carbamates for use in thepreparation of a medicament for the treatment of disorders mediated by amitogen activated protein kinase.

The invention further includes a compound of formula (I) or one of itspharmaceutically acceptable salts, prodrugs, biohydrolyzable esters,amides, carbonates, amines, ureides or carbamates for use in thepreparation of a medicament for the treatment of disorders mediated bycRaf kinase.

A group of preferred species of compounds of the present inventioncomprises the group:

Another group of preferred compounds of the invention comprises thegroup.

Still another group of preferred compounds comprises the group:

An especially preferred group of compounds comprises the group:

Independent Substituents

The invention discloses eight different points of substitution onstructural formula (I). Each of these points of substitution bears asubstituent whose selection and synthesis as part of this invention wasindependent of all other points of substitution on formula (I). Thus,each point of substitution is now further described individually.

R¹ is hydrogen. Optionally, R¹ can be joined with an R² substituent toform a fused ring. Such fused rings can be five to ten membered aryl,heteroaryl, or heterocyclyl rings or ring systems, having 1 to 3heteroatoms. These heteroatoms can be nitrogen, oxygen or sulfur. Suchfused rings can be optionally substituted by one to three groups ofhalogen, cyano, nitro, substituted amide, substituted sulfonamide,substituted amine, substituted ether or hydroxyl. Substitutents for amides, sulfonamides, amines, or ethers include hydrogen, halogen, 1 to 12carbon aliphatic (which can bear an insertede group anywhere along itschain length of an oxygen, a sulfur, a sulfoxide, a sulfone, a sulfine,or a secondary amine), aryl rings, heterocyclic ring. Substituents onthese aliphatic aryl or heterocyclic groups include 1 to 3 substitutionsby a halogen, another heterocyclic ring, another aryl ring, cyano,substituted sulfo, substituted oxy, substituted amine, substitutedsulfoxide, substituted sulfine, substituted sulfone, substitutedsulfonamide, substituted amide, substituted ureide, substituted ester,substituted carbamate. These substituents in turn can be 1 to 12 carbonaliphatic or a heterocyclic ring, where the 1 to 12 carbon aliphaticitself can be substituted by 1 to 3 occurences of a halogen, orhydroxyl.

Alternatively, R¹ can be hydrogen or optionally, R¹ can be joined withan R² substituent to form a fused ring. Such fused rings can be from thegroup comprising benzofuran, benzoxazole, dioxin, dioxane, dioxolane,dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, indole,indazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine,oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole,pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, quinazoline,tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine,thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine,thianaphthalene, thiopyran, triazine, and triazole. Any of these ringscan in turn be substituted by a group from the substituents comprising 1to 3 substitutions by a halogen, another heterocyclic ring, another arylring, cyano, substituted sulfo, substituted oxy, substituted amine,substituted sulfoxide, substituted sulfine, substituted sulfone,substituted sulfonamide, substituted amide, substituted ureide,substituted ester, or substituted carbamate. These substituents in turncan be 1 to 12 carbon aliphatic or a heterocyclic ring, where the 1 to12 carbon aliphatic itself can be substituted by 1 to 3 occurences of ahalogen, or hydroxyl.

Preferably, R¹ is hydrogen or fused with R² to form fused pyridine,fused triazole, fused thiazole or fused amino-substituted thiazole.

Most preferably, R¹ is hydrogen.

R² is hydrogen, an aryl ring, a heterocyclic ring, a 1 to 12 carbonaliphatic, cyano, nitro, halogen, substituted ether, substitutedthioether, substituted sulfine, substituted sulfone, substituted amine,disubstituted amine, substituted amide, substituted carbamate,substituted sulfonamide, substituted carbonyl, or substituted ester.These substituents can be hydrogen, halogen, 1 to 12 carbon aliphatic(which can bear an inserted group anywhere along its chain length of anoxygen, a sulfur, a sulfoxide, a sulfone, a sulfine, or a secondaryamine), aryl rings, heterocyclic rings. Substituents on these aliphatic,aryl or heterocyclic groups include 1 to 3 substitutions by a halogen,another heterocyclic ring, another aryl ring, cyano, substituted sulfo,substituted oxy, substituted amine, substituted sulfoxide, substitutedsulfine, substituted sulfone, substituted sulfonamide, substitutedamide, substituted ureide, substituted ester, substituted carbamate.These substituents in turn can be 1 to 12 carbon aliphatic or aheterocyclic ring, where the 1 to 12 carbon aliphatic itself can besubstituted by 1 to 3 occurences of a halogen, or hydroxyl.

R² can be joined with R³ to form a fused ring selected from the groupcomprising benzofuran, benzoxazole, dioxin, dioxane, dioxolane,dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, indole,indazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine,oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole,pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, quinazoline,tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine,thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine,thianaphthalene, thiopyran, triazine, and triazole.

R² can more preferably be hydrogen, a heterocyclic ring, phenyl, a 1 to6 carbon aliphatic, a substituted amine, a substituted carbonyl, asubstituted ester, a substituted amide, or a substituted sulfonamide.Said heterocyclic ring, phenyl or aliphatic group are optionallysubstituted by amino or 1 to 6 carbon aliphatic. Said amine, carbonyl,ester amide or sulfonamide are optionally substituted by 1 to 6 carbonaliphatic, amino, hydroxy-aliphatic of 1 to 6 carbons, phenyl,phenyl-aliphatic of 1 to 6 carbons, amino-aliphatic of 1 to 12 carbonsor heterocyclic rings such as oxazole, pyridine, tetrazole or thiazole.

R² can more preferably be joined with R³ to form a five membered fusedring having a heteroatom of either nitrogen, oxygen or sulfur. Thesefused rings can be substituted by 1 to 6 carbon aliphatic, or a 1 to 6carbon acyl group.

R² can also more preferably be hydrogen, thiophene, pyridine, phenyl, 1to 6 carbon aliphatic, cyano, halogen, substituted acyl, or substitutedamide. These substituents can be 1 to 6 carbon aliphatic, tri-halogen 1to 6 carbon aliphatic, phenyl, nitro-substituted phenyl, orhydroxy-aliphatic of 1 to 6 carbons.

R² is hydrogen, an aryl ring, a heterocyclic ring, a 1 to 12 carbonaliphatic, cyano, nitro, halogen, substituted ether, substitutedthioether, substituted sulfine, substituted sulfone, substituted amine,disubstituted amine, substituted amide, substituted carbamate,substituted sulfonamide, substituted carbonyl, or substituted ester.These substituents can be hydrogen, halogen, 1 to 12 carbon aliphatic(which can bear an inserted group anywhere along its chain length of anoxygen, a sulfur, a sulfoxide, a sulfone, a sulfine, or a secondaryamine), aryl rings, heterocyclic rings. Substituents on these aliphatic,aryl or heterocyclic groups include 1 to 3 substitutions by a halogen,another heterocyclic ring, another aryl ring, cyano, substituted sulfo,substituted oxy, substituted amine, substituted sulfoxide, substitutedsulfine, substituted sulfone, substituted sulfonamide, substitutedamide, substituted ureide, substituted ester, substituted carbamate.These substituents in turn can be 1 to 12 carbon aliphatic or aheterocyclic ring, where the 1 to 12 carbon aliphatic itself can besubstituted by 1 to 3 occurences of a halogen, or hydroxyl.

R³ can be joined with R² to form a fused ring selected from the groupcomprising benzofuran, benzoxazole, dioxin, dioxane, dioxolane,dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, indole,indazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine,oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole,pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, quinazoline,tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine,thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine,thianaphthalene, thiopyran, triazine, and triazole.

R³ can more preferably be hydrogen, a heterocyclic ring, phenyl, a 1 to6 carbon aliphatic, a substituted amine, a substituted carbonyl, asubstituted ester, a substituted amide, or a substituted sulfonamide.Said heterocyclic ring, phenyl or aliphatic group are optionallysubstituted by amino or 1 to 6 carbon aliphatic. Said amine, carbonyl,ester amide or sulfonamide are optionally substituted by 1 to 6 carbonaliphatic, amino, hydroxy-aliphatic of 1 to 6 carbons, phenyl,phenyl-aliphatic of 1 to 6 carbons, amino-aliphatic of 1 to 12 carbonsor heterocyclic rings such as oxazole, pyridine, tetrazole or thiazole.

R³ can more preferably be joined with R² to form a five membered fusedring having a heteroatom of either nitrogen, oxygen or sulfur. Thesefused rings can be substituted by 1 to 6 carbon aliphatic, or a 1 to 6carbon acyl group.

R³ can also more preferably be hydrogen, thiophene, pyridine, phenyl, 1to 6 carbon aliphatic, cyano, halogen, substituted acyl, or substitutedamide. These substituents can be 1 to 6 carbon aliphatic, tri-halogen 1to 6 carbon aliphatic, phenyl, nitro-substituted phenyl, orhydroxy-aliphatic of 1 to 6 carbons.

R⁴ is hydrogen, nitro, cyano, or halogen.

Preferably, R⁴ is hydrogen.

R⁵ is hydrogen or 1 to 12 carbon aliphatic, which is optionallysubstituted at 1 to 3 positions by a halogen, hydroxyl, or an aryl ring.

R⁵ is alternatively hydrogen or 1 to 6 carbon aliphatic, which isoptionally substituted at 1 to 3 positions by a halogen, hydroxyl or anaryl ring.

Preferably, R⁵ is hydrogen.

R⁶ is halogen, cyano, nitro, substituted amide, substituted sulfonamide,substituted amine, substituted ether or hydroxyl. Substitutents foramides, sulfonamides, amines, or ethers include hydrogen, halogen, 1 to12 carbon aliphatic (which can bear an inserted group anywhere along itschain length of an oxygen, a sulfur, a sulfoxide, a sulfone, a sulfine,or a secondary amine), aryl rings, heterocyclic rings. Substituents onthese aliphatic, aryl or heterocyclic groups include 1 to 3substitutions by a halogen, another heterocyclic ring, another arylring, cyano, substituted sulfo, substituted oxy, substituted amine,substituted sulfoxide, substituted sulfine, substituted sulfone,substituted sulfonamide, substituted amide, substituted ureide,substituted ester, substituted carbamate. These substituents in turn canbe 1 to 12 carbon aliphatic or a heterocyclic ring, where the 1 to 12carbon aliphatic itself can be substituted by 1 to 3 occurences of ahalogen, or hydroxyl.

R⁶ is more preferably a halogen.

R⁶ is most preferably a bromine.

Alternatively, R⁶ is most preferably a chlorine.

R⁷ is halogen, cyano, nitro, substituted amide, substituted sulfonamide,substituted amine, substituted ether or hydroxyl. Substitutents foramides, sulfonamides, amines, or ethers include hydrogen, halogen, 1 to12 carbon aliphatic (which can bear a n inserted group anywhere alongits chain length of an oxygen, a sulfur, a sulfoxide, a sulfone, asulfine, or a secondary amine), aryl rings, heterocyclic rings.Substituents on these aliphatic, aryl or heterocyclic groups include 1to 3 substitutions by a halogen, another heterocyclic ring, another arylring, cyano, substituted sulfo, substituted oxy, substituted amine,substituted sulfoxide, substituted sulfine, substituted sulfone,substituted sulfonamide, substituted amide, substituted ureide,substituted ester, substituted carbamate. These substituents in t urncan be 1 to 12 carbon aliphatic or a heterocyclic ring, where the 1 to12 carbon aliphatic itself can be substituted by 1 to 3 occurences of ahalogen, or hydroxyl.

R⁷is more preferably a halogen.

R⁷ is most preferably a bromine.

Alternatively, R⁷ is most preferably a chlorine.

R⁸is hydroxy or sulfonamide optionally substituted by a 1 to 12 carbonaliphatic, or substituted by a heterocyclic ring. This aliphatic groupitself can be substituted by 1 to 3 halogens or hydroxy.

Alternatively, R⁸ is hydroxy or NHCOCF₃, or sulfonamide optionallysubstituted by a 1 to 6 carbon aliphatic, or substituted by aheterocyclic ring.

Or, R⁸ is hydroxy or NHCOCF3, or sulfonamide optionally substituted by a1 to 6 carbon aliphatic, a nitro, a 1 to 6 carbon alkoxy, a halogen, anaryl or a hetercyclic ring. This aliphatic group itself be substitutedby 1 to 3 halogens or hydroxy.

Preferably, R⁸ is hydroxy.

In further aspect, the present invention provides a process for thepreparation of a compound of the formula (I), which process comprisesthe reaction of a compound of the formula (II)

with a compound of the formula (III)

The reaction is conveniently carried out in the presence of a catalyticacid in the presence of a suitable inert solvent, for example anaromatic hydrocarbon or a halogenated hydrocarbon at a non-extremetemperature, for example from 0° C. to 150°C., preferably 80°C. to110°C. Optionally the reaction is carried out in the presence of astrong acid, for example hydrochloric acid or sulfuric acid, in aceticacid as the solvent.

The preparation of compounds (II) and (III) is well known to thoseskilled in the art and many compounds having formula (II) arecommercially available. (P. G. Gassman; T. J. vanBergen, Oxindoles. ANew General Method of Synthesis. Journal of the American ChemicalSociety, 96 (17), 1974, 5508-5512.) ( Jutz, Adv. Org. Chem., 9, 225-342,1975; Truce, Org. React., 9, 37-72. 1957).

In addition to the above, one compound of formula (I) may be convertedto another compound of formula (I) by chemical transformation of theappropriate substituent or substituents.

The present invention also provides compounds of formula (I) andpharmaceutically acceptable salts, prodrugs, biohydrolyzable esters,amides, carbonates, amines, ureides or carbamates thereof (hereinafteridentified as the ‘active compounds’) for use in medical therapy, andparticularly in the treatment of disorders mediated by protein kinaseactivity such as human malignancies. The compounds are especially usefulfor the treatment of disorders which are caused by mutated ras andupregulated tyrosine kinase signalling pathways such as breast, colon,lung, pancreatic, prostate, and gastric cancers.

The present invention also provides a method of treating a diseasemediated by a kinase selected from the group consisting of ab1, ATK ,bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6,CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2,FGFR3, FGFR4, FGFR5, Fgr, FLK4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, cRaf1, p38, PDGFR, PIK, PKC, PYK2, ros,tie₁, tie₂, TRK, Yes, and Zap70, said method comprising the step ofadministering to a mammal in need thereof a pharmacologically effectiveamount of an active compound as defined above.

A further aspect of the invention provides a method of treatment of thehuman or animal body suffering from a disorder mediated by a mitogenactivated protein kinase which comprises administering an effectiveamount of an active compound as defined above to the human or animalpatient.

The present invention particularly provides a method of treating adisease meditated by cRaf1 kinase, said method comprising the step ofadministering to a mammal in need thereof a pharmacologically effectiveamount of an active compound as defined above.

The present invention also provides a method of inhibiting tumor growth,preventing organ transplant rejection, healing a chronic wound, or oftreating a disease state selected from the group consisting ofrestenosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis,atherosclerosis, glomerulonephritis, diabetic nephropathy, malignantnephrosclerosis, thrombotic microangiopathy syndromes, glomerulopathy,psoriasis, diabetes mellitus, inflammation, and neurodegenerativedisease, comprising the step of administering to a patient in needthereof a pharmacologically effective amount of an active compound asdefined above.

Another aspect of the present invention provides the use of an activecompound of formula (I), in the preparation of a medicament for thetreatment of malignant tumors.

Another aspect of the present invention provides the use of an activecompound of formula (I), in coadministration with previously knownanti-tumor therapies for more effective treatment of such tumors.

The active compounds of the formula (I) have anticancer activity asdemonstrated hereinafter by their inhibition of the proteinserine/threonine kinase c-Raf1 enzyme. It has thus been established thatcompounds of the present invention are of use in medicine and, inparticular in the treatment of certain human malignancies, for examplebreast, ovarian, non-small cell lung, pancreatic, gastric and coloncancers. Accordingly, the present invention provides a method for thetreatment of susceptible malignancies in an animal, e.g. a human, whichcomprises administering to the animal a therapeutically effective amountof an active compound as defined above.

Compounds we have synthesized as part of the present invention which arecurrently preferred are listed in Tables 1A, 1B and 1C below. Compoundsare identified by the numbers shown in the first column; variables belowin the rest of the columns are with reference to the generic structure(I). Corresponding IUPAC nomenclature are disclosed in Tables 2A, 2B and2C, respectively, below. Since all substituents at each point ofsubstitution are capable of independent synthesis of each other, Tables1A, 1B and 1C are also to be read as a matrix in which any combinationof substituents is within the scope of the disclosure and claims of theinvention.

TABLE 1A

# R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸  1 H CN H H H Br Br OH  2 H

H H H Br Br OH  3 H

H H H Br OEt OH  4 H

H H H Cl Cl OH  5 H

H H H Br Br OH  6 H

H H H Br Br OH  7 H

H H H Cl Cl OH  8 H

H H H Br OEt OH  9 H

H H H Cl Cl OH  10 H

H H H Br OEt OH  11 H

H H H Br Br OH  12 H

H H H Cl Cl OH  13 H

H H H Br Br OH  14 H

H H H Br OEt OH  15 H

H H H Cl Cl OH  16 H

H H H Br OEt OH  17 H

H H H Cl Cl OH  18 H

H H H Br Br OH  19 H

H H H Br Br OH  20 H CO₂Me H H H Br Br OH  21 H

H H H Br Br OH  22 H

H H H Cl Cl OH  23 H

H H H Br OEt OH  24 H

H H H Br Br OH  25 H

H H H Br Br OH  26 H

H H H Br Br OH  27 H CO₂Me H H H Cl Cl OH  28 H H H H H Br Br OH  29 H

H H H Br Br OH  30 H

H H H Br Br OH  31 H

H H H Br Br OH  32 H

H H H Br Br OH  33 H

H H H Br Br OH  34 H

H H H Br Br OH  35 H

H H H Br Br OH  36 H

H H H Br Br OH  37 H

H H H Br Br OH  38 H Cl H H H Br Br OH  39 H Cl H H H Cl Cl OH  40 HCF₃O H H H Br Br OH  41 H Br H H H Cl Cl OH  42 H I H H H Br OEt OH  43H I H H H Br OMe OH  44 H Br H H H I I OH  45 H CF₃O H H H I I OH  46 HH H H H Br OMe OH  47 H H H H H NO₂ NO₂ OH  48 H H H H H Cl Cl OH  49 HH H H H Cl OMe OH  50 H H H H H I I OH  51 H Cl H H H Br OMe OH  52 H ClH H H NO₂ NO₂ OH  53 H Cl H H H OMe NO₂ OH  54 H Cl H H H Cl OMe OH  55H Cl H H H I I OH  56 H Br H H H Br OEt OH  57 H Br H H H Br OMe OH  58H F F H H Br OMe OH  59 H CF₃O H H H Br OEt OH  60 H CF₃O H H H Cl Cl OH 61 H CF₃O H H H Br OMe OH  62 H NO₂ H NO₂ H Br Br OH  63 H NO₂ H H H BrBr OH  64 H H H I H Br Br OH  65 H NO₂ H H H Cl Cl OH  66 H H H I H BrBr OH  67 H H H Br H Cl Cl OH  68 H NO₂ H H H Br OEt OH  69 H

H H H Br Br OH  70 H

H H H Br Br OH  71 H

H H H Br Br OH  72 H

H H H Br Br OH  73 H

H H H Br Br OH  74 H

H H H Br Br OH  75 H

H H H Br Br OH  76 H

H H H Br Br OH  77 H

H H H Br Br OH  78 H

H H H Br Br OH  79 H I H H H Br Br OH  80 H I H H H Br Br

 81 H Br H H H Br Br OH  82 H Br H H H Cl OMe OH  83 H

H H H Br Br OH  84 H

H H H Br Br OH  85 H

H H H Cl Cl OH  86 H

H I H Br Br OH  87 H I H H H Br Br

 88 H

H H H Cl Cl OH  89 H

H H H Br Br OH  90 H

H H H Cl Cl OH  91 H

H H H Br Br OH  92 H

H H H Br Br OH  93 H

H H H Cl Cl OH  94 H

H H H Br Br OH  95 H

H H H Br Br OH  96 H

H H H Br Br OH  97 H

H H H Br Br OH  98 H

H H H Cl Cl OH  99 H

H H H Cl Cl OH 100 H

H H H Cl Cl OH 101 H H H H H NO₂ OMe OH 102 H H H H H OMe I OH 103 H ClH H H Br Br OAc 104 H I H H H OMe NO₂ OH 105 H NO₂ H H H Cl OH OH 106 HCl H H H Br Br

107 H

H H H Br Br OH 108 H

H H H Br Br OH 109 H H H F H Br Br OH 110 H

H H H Br Br OH 111 H

H H H Br OEt OH 112 H H

H H Br Br OH 113 H H

H H Br Br OH 114 H

H H H I I OH 115 H

H H H Cl Cl OH 116 H

H H H Cl Cl OH 117 H

H H H Br Br

118 H —N(Ac)CH2CH2— H H Br Br OH 119 —CH═CH—CH═N— H H H Br Br OH 120 HEt H H H Br Br OH 121 —S—CH═N— H H H Br Br OH 122 H CF₃CO H H H Br Br OH123 H H Br H H Br Br OH 124 H

H H H Cl Cl OH 125 H

H H H Br Br OH 126 H

H H H Br Br OH 127 H

H H H Cl Cl OH 128 H

H H H Cl Cl OH 129 H

H H H Br Br OH 130 H

H H H NO₂ NO₂ OH 131 H H H H H NO₂ NO₂ OH 132 —N═N—N— H H H Br Br OH 133H H Br H H Cl Cl OH 134 H

H H H Cl Cl OH 135 —N═C(NH₂)—S— H H H Br Br OH 136 H

H H H Br Br OH 137 H

H H H Br Br OH 138 H

H H H Br Br OH 139 H

H H H Br Br OH 140 H

H H H Br Br OH 141 H

H H H Cl Cl OH 142 H

H H H Br Br OH 143 H

H H H Br Br OH 144 H

H H H Br Br OH 145 H

H H H Br Br OH

TABLE 1B # R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ 157 H

H H H Br Br OH 162 H

H H H Br Br OH 163 H (CH₃)₂N H H H Br Br OH

TABLE 1B # R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ 157 H

H H H Br Br OH 162 H

H H H Br Br OH 163 H (CH₃)₂N H H H Br Br OH

TABLE 2 # Chemical Name 13-(3,5-Dibromo-4-hydroxy-benzylidine-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile 23-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one 33-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene)-5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one 43-(3,5-Dichloro-4-hydroxy-benzylidene-5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one (butanoyl)-1,3-dihydro-indol-2-one 53-(3,5-Dibromo-4-hydroxy-benzylidene-5-(3-methyl-butanoyl-1,3-dihydro-indol-2-one 65-Benzoyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3 dihydro-indol-2-one7 5-Benzoyl-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 85-Benzoyl-3-(3-bromo-5-ethoxy-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 93-(3,5-Dichloro-4-hydroxy-benzylidene-5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one 103-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene)-5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one 113-(3,5-Dibromo-4-hydroxy-benzylidene-5-(pyridine-3-carbonyl)-1,3-dihydro-indol-2-one 123-(3,5-Dichloro-4-hydroxy-benzylidiene)-5-(pyridine-3-carbonyl)-1,3-dihydro-indol-2-one 133-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(pyridine-4-carbonyl)-1,3-dihydro-indol-2-one 143-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene)-5-(pyridine-4-carbonyl)-1,3-dihydro-indol-2-one 153-(3,5-Dichloro-4-hydroxy-benzylidene)-5-(pyridine-4-carbonyl)-1,3-dihydro-indol-2-one 163-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene)-5-(pyridine-3-carbonyl)-1,3-dihydro-indol-2-one 173-(3,5-Dichloro-4-hydroxy-benzylidene-5-(oxazol-5-yl)-1,3-dihydro-indol-2-one 183-(3,4-Dibromo-4-hydroxy-benzylidene)-5-(oxazol-5-yl)-1,3-dihydro-indol-2-one 193-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-ethyl-thiazol-4-yl)-1,3-dihydro-indol-2-one 203-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylic acid methyl ester 213-(3,5-Dibromo-4-hydroxy-benzylidene-5-(furan-2-carbonyl)-1,3-dihydro-indol-2-one 223-(3,5-Dichloro-4-hydroxy-benzylidene-5-(furan-2-carbonyl)-1,3-dihydro-indol-2-one 233-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene-5-(furan-2-carbonyl)-1,3-dihydro-indol-2-one 245-Cyclopropanecarbonyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 255-Aminomethyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 265-Cyclopentanecarbonyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 273-(3,5-Dichloro-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester 283-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro- indol-2-one 293-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(thiophene-2-carbonyl)-1,3-dihydro-indol-2-one 305-(2-Amino-thiazol-4-yl)-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 313-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(imidazo[1,2a]pyridin-2-yl)-1,3-dihydro-indol-2-one 323-(3,5-Dibromo-4-hydroxy-benzylidene)-5-propionyl-1,3-dihydro-indol-2-one 33 3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide 343-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3dihydro-1H-indole-5-sulfonic acid N,N-diethylamide 353-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(pyrrolidine-1-sulfonyl)-1,3-dihydro-indol-2-one 363-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-sulfonic acid (N-2-dimethylamino-ethyl)-N-methyl-amide 373-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(isoxazole-5-carbonyl)-1,3-dihydro-indol-2-one 385-Chloro-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one39 5-Chloro-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 40 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-trifluoromethoxy-1,3-dihydro-indol-2-one 415-Bromo-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one42 3-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene)-5-iodo-1,3-dihydro-indol-2-one 433-(3-Bromo-4-hydroxy-5-methoxy-benzylidene)-5-iodo-1,3-dihydro-indol-2-one 445-Bromo-3-(3,5-diiodo-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one 453-(3,5-diiodo-4-Hydroxy-benzylidene)-5-trifluoromethoxy-1,3-dihydro-indol-2-one 463-(3-Bromo-4-hydroxy-5-methoxy-benzylidene)-1,3- dihydro-indol-2-one 473-(3,5-dinitro-4-Hydroxy-benzylidene)-1,3-dihydro-indol- 2-one 483-(3,5-dichloro-4-Hydroxy-benzylidene)-1,3-dihydro- indol-2-one 493-(3-Chloro-4-hydroxy-5-methoxy-benzylidene)-1,3- dihydro-indol-2-one 503-(3,5-diiodo-4-Hydroxy-benzylidene)-1,3-dihydro-indol- 2-one 513-(3-Bromo-4-hydroxy-5-methoxy-benzylidene)-5-chloro-1,3-dihydro-indol-2-one 525-Chloro-3-(3,5-dinitro-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one53 5-Chloro-3-(4-hydroxy-3-methoxy-5-nitro-benzylidene)-1,3-dihydro-indol-2-one 545-Chloro-3-(3-chloro-4-hydroxy-5-methoxy-benzylidene)-1,3-dihydro-indol-2-one 555-Chloro-3-(3,5-diiodo-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one56 5-Bromo-3-(3-bromo-5-ethoxy-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 575-Bromo-3-(3-bromo-4-hydroxy-5-methoxy-benzylidene)-1,3-dihydro-indol-2-one 583-(3-Bromo-4-hydroxy-5-methoxy-benzylidene)-5,6-difluoro-1,3-dihydro-indol-2-one 593-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene)-5-trifluoromethoxy-1,3-dihydro-indol-2-one 603-(3,5-Dichloro-4-hydroxy-benzylidene)-5-trifluoromethoxy-1,3-dihydro-indol-2-one 613-(3-Bromo-4-hydroxy-5-methoxy-benzylidene)-5-trifluoromethoxy-1,3-dihydro-indol-2-one 623-(3,5-Dibromo-4-hydroxy-benzylidene)-5,7-dinitro-1,3-dihydro-indol-2-one 633-(3,5-Dibromo-4-hydroxy-benzylidene)-5-nitro-1,3- dihydro-indol-2-one64 3-(3,5-Dibromo-4-hydroxy-benzylidene)-7-iodo-1,3- dihydro-indol-2-one65 3-(3,5-Dichloro-4-hydroxy-benzylidene)-5-nitro-1,3-dihydro-indol-2-one 66 3-(3,5-dibromo-4-hydroxy-benzylidene)-7-iodo-1,3-dihydro-indol-2-one 677-Bromo-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one68 3-(3-Bromo-5-ethoxy-4-hydroxy-benzylidene)-5-nitro-1,3-dihydro-indol-2-one 69 2-(N-{3-[3-(3,5Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-2-oxo-ethyl}-N-methyl-amino)- acetamide 703-(3,5-Dibromo-4-hydroxy-benzylidene)-5-{2-[(N-2-hydroxy-ethyl)-N-(3-hydroxy-propyl)-amino]-acetyl}-1,3-dihydro-indol-2-one 71 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(3-methylimidazol-1-yl-acetyl)-1,3-dihydro-indol-2-one 723-(3,5-Dibromo-4-hydroxy-benzylidene-5-(2-(thiomorpholin-4-yl)-acetyl)-1,3-dihydro-indol-2-one 733-(3,5-Dibromo-4-hydroxy-benzylidene-5-(2-morpholin-4-yl-acetyl)-1,3-dihydro-indol-2-one 745-{2-[Bis-(2-hydroxy-ethyl)-amino]-acetyl}-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 753-(3,5-Dibromo-4-hydroxy-benzylidene)-5-{2-[N-(2-hydroxy-ethyl)-N-methyl-amino]-acetyl-1,3-dihydro-indol- 2-one 763-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-(thiazolidin-3-yl)-acetyl)-1,3-dihydro-indol-2-one 773-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-(N-pyridinium)-acetyl)-1,3-dihydro-indol-2-one chloride 785-{2-[N-Benzyl-N-(2-hydroxy-acetyl)-amino]-ethyl}-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 793-(3,5-Dibromo-4-hydroxy-benzylidene)-5-iodo-1,3- dihydro-indol-2-one 802,2-Dimethyl-propionic acid,2,6-dibromo-4-(5-iodo-2-oxo-1,3-dihydro-indol-3-ylidenemethyl)-phenoxymethyl ester 815-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one82 5-Bromo-3-(3-chloro-4-hydroxy-5-methoxy-benzylidene)-1,3-dihydro-indol-2-one 83 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-diethylamino-acetyl)-1,3-dihydro-indol-2-one 845-(2-Chloro-acetyl)-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 853-(3,5-Dichloro-4-hydroxy-benzylidene)-5-(2-diethylamino-acetyl)-1,3-dihydro-indol-2-one 865-(2-Chloro-acetyl)-3-(3,5-dibromo-4-hydroxy-benzylidene)-7-iodo-1,3-dihydro-indol-2-one 87N-[bis-(2-hydroxy-ethyl)]carbamic acid, 2,6-dibromo-4-(5-iodo-2-oxo-1,3-dihydro-indol-3-ylidenemethyl) phenyl ester 885-(2-Chloro-acetyl)-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 895-Acetyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one90 5-Acetyl-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 913-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(3-methoxy-benzoyl)-1,3-dihydro-indol-2-one 923-(3,5-Dibromo-4-hydroxy-benzylidene)-5-phenyl-1,3- dihydro-indol-2-one93 3-(3,5-Dichloro-4-hydroxy-benzylidene)-5-phenyl-1,3-dihydro-indol-2-one 94 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-(ethylamino)-4H-thiazol-4-yl)-1,3-dihydro-indol-2-one 953-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(4-nitro-benzoyl)-1,3-dihydro-indol-2-one 963-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(3-nitro-benzoyl)-1,3-dihydro-indol-2-one 973-(3,5-Dibromo-4-hydroxy-benzylidene)-5-((hydroxyimino)-phenyl-methyl)-1,3-dihydro-indol-2-one 983-(3,5-Dichloro-4-hydroxy-benzylidene)-5-propionyl-1,3-dihydro-indol-2-one 99 3-(3,5-Dichloro-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide 1003-(3,5-Dichloro-4-hydroxy-benzylidene)-5-(pyrrolidine-1-sulfonyl)-1,3-dihydro-indol-2-one 1013-(4-Hydroxy-3-methoxy-5-nitro-benzylidene)-1,3- dihydro-indol-2-one 1023-(4-Hydroxy-3-iodo-5-methoxy-benzylidene)-1,3- dihydro-indol-2-one 1032,6-Dibromo-4-[(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl acetate 1043-(4-Hydroxy-3-methoxy-5-nitro-benzylidene)-5-iodo-1,3-dihydro-indol-2-one 1053-(3-Chloro-4,5-dihydroxy-benzylidene)-5-nitro-1,3- dihydro-indol-2-one106 2,6-Dibromo-4-[(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl N,N-diisopropylcarbamate 1073-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-dimethylamino-acetyl)-1,3-dihydro-indol-2-one 1083-(3,5-Dibromo-4-hydroxy-benzylidene)-5-{2-[N-ethyl-N-(2-hydroxy-ethyl)-amino]-acetyl}-1,3-dihydro-indol-2-one 1093-(3,5-Dibromo-4-hydroxy-benzylidene)-7-fluoro-1,3- dihydro-indol-2-one110 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-[2-(4-methyl-piperazin-1-yl)-acetyl]-1,3-dihydro-indol-2-one (hydrochloride salt) 1113-(3-Bromo-4-hydroxy-5-ethoxy-benzylidene)-5-(2-dimethylamino-acetyl)-1,3-dihydro-indol-2-one 1123-(3,5-Dibromo-4-hydroxy-benzylidene)-6-phenyl-1,3- dihydro-indol-2-one113 3-(3,5-Dibromo-4-hydroxy-benzylidene)-6-isopropoxy-1,3-dihydro-indol-2-one 114 5-(2-Chloro-acetyl)-3-(3,5-diiodo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 1153-(3,5-Dichloro-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-sulfonic acid diethylamide 1163-(3,5-Dichloro-4-hydroxy-benzylidene)-5-(morpholine-4-sulfonyl)-1,3-dihydro-indol-2-one 117N-diethyl-2,6-dibromo-4-[(5-pyridine-3-carbonyl)-2-oxo-1,3-dihydro-indol-3-ylidenemethyl]phenyl ester 1185-Acetyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-3,5,6,7-tetrahydro-1H-pyrrolo[2,3-f]indol-2-one 1191-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro-pyrrolo[3,2-f]quinolin-2-one 1203-(3,5-Dibromo-4-hydroxy-benzylidine)-5-ethyl-1,3- dihydro-indol-2-one121 8-(3,5-Dibromo-4-hydroxy-benzylidine)-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one 122(3,5-Dibromo-4-hydroxy-benzylidene)-5-trifluoromethoxy-1,3-dihydro-indol-2-one 1236-Bromo-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one124 3-(3,5-Dichloro-4-hydroxy-benzylidene)-5-(2-phenyl-thiazol-4-yl)-1,3-dihydro-indol-2-one 1253-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-phenyl-thiazol-4-yl)-1,3-dihydro-indol-2-one 1263-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-phenylamino-thiazol-4-yl)-1,3-dihydro-indol-2-one 1273-(3,5-Dichloro-4-hydroxy-benzylidene)-5-(2-phenylamino-thiazol-4-yl)-1,3-dihydro-indol-2-one 1283-(3,5-Dichloro-4-hydroxy-benzylidene)-5-(3-thioxo-2,3,4,5-tetrahydro-[1,2,4]-triazine-6-yl)-1,3-dihydro-indol- 2-one 1293-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(3-thioxo-2,3,4,5-tetrahydro-[1,2,4]-triazine-6-yl)-1,3-dihydro-indol- 2-one 1303-(3,5-Dinitro-4-hydroxy-benzylidene)-5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one 1313-(3,5-Dinitro-4-hydroxy-benzylidene)-1,3-dihydro-indol- 2-one 1328-(3,5-Dibromo-4-hydroxy-benzylidene)-6,8-dihydro-3H-1,2,3,6-tetraaza-as-indacen-7-one 1336-Bromo-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3- dihydro-indol-2-one134 5-(2-Amino-thiazol-4-yl)-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 1352-Amino-8-(3,5-dibromo-4-hydroxy-benzylidene)-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one 1365-(N-Acetyl-2-amino-thiazol-4-yl)-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one 1373-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylic acid amide 1383-(3,5-Dibromo-4-hydroxy-benzylidene)-5-pyrid-3-yl-1,3-dihydro-indol-2-one 1393-(3,5-Dibromo-4-hydroxy-benzylidene)-5-thiophen-3-yl-1,3-dihydro-indol-2-one 140 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-methylamino-thiazol-4-yl-1,3-dihydro-indol-2-one 1413-(3,5-Chloro-4-hydroxy-benzylidene)-5-(2-methylamino-thiazol-4-yl-1,3-dihydro-indol-2-one 1423-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(1H-tetrazol-5-yl)-1,3-dihydro-indol-2-one 1433-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-methyl-2H-tetrazol-5-yl)-1,3-dihydro-indol-2-one 144N[bis(2-Hydroxyethyl)]-carbamic acid 2,6 dibromo-4-[5-(2-methyl-thiazol-4-yl)-2-oxo-1,2-dihydro-indol-3- ylidenemethyl]-phenylester 145 3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,3-dihydro-indol-2-one 1573-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-N,N-bis(2-hydroxyethyl)-2-oxo-5-indolinesulfonamide 162N-Benzyl-3-[(3,5-dibromo-4-hydroxyphenyl)methylidene]-2-oxo-5-indolinecarboxamide 1633-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-5-(dimethylamino)-1,3-dihydro-2H-indol-2-one 146 Benzyl2,6-dibromo-4-[(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl carbonate 1472,6-Dibromo-4-[(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl ethyl carbonate 1482,6-Dibromo-4-[(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl isobutyl carbonate 1492,6-Dibromo-4-[(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl 3-pyridinylmethyl carbonate 1502,6-Dibromo-4-[(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenoxymethyl pivalate 1512,6-Dibromo-4-[(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl 4-morpholinecarboxylate 1522,6-Dibromo-4-[(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl N-[2-(2- hydroxyethoxy)ethyl]carbamate 1532,6-Dibromo-4-[(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl 4-methyltetrahydro-1(2H)- pyrazinecarboxylate 1542,6-Dibromo-4-[(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl N,N-diethylcarbamate 1552,6-Dibromo-4-[(5-glycoloyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl ethyl carbonate 1563-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylic acid 158N-3-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylbenzamide 159N-3-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylbenzamide 160N-3-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl-2-hydroxyacetamide 1613-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-2-oxo-N-(3-phenylpropyl)-5-indolinecarboxamide 1644-[5-(Aminosulfonyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]methyl-2,6-dibromophenyl N,N-diethylcarbamate 1651-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-7-methyl-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one 1665-Amino-3-[(3,5-dibromo-4-hydroxyphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 1674-[(5-Benzoyl-2-oxo-1,2-dihydro-3H-indol-3-yildene)methyl]-2,6-dibromophenyl N,N-diethylcarbamate 1683-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-N-(2-(dimethylamino)ethyl]-2-oxo-5-indolinecarboxamide 1695-[3,5-bis(Trifluoromethyl)phenyl]-3-[(3,5-dibromo-4-hydroxyphenyl)methylidene]-1,3-dihydro-2H-indol-2-one 1703-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-5-(3-thienyl)-1,3-dihydro-2H-indol-2-one 1713-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-5-(2,4-dichlorophenyl)-1,3-dihydro-2H-indol-2-one 1723-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-N-(2-hydroxyethyl)-2-oxo-5-indolinecarboxamide 1733-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-5-[2-(dimethylamino)-1,3-thiazol-4-yl]-1,3-dihydro-2H-indol-2- one 1743-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-5-(methylsulfonyl)-1,3-dihydro-2H-indol-2-one 1754-3-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-2-oxo2,3-dihydro-1H-indol-5-ylbenzenesulfonamide 1763-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-6-vinyl-1,3-dihydro-2H-indol-2-one 177 Methyl 3-3-[(3,5dibromo-4-hydroxyphenyl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl-2-thiophenecarboxylate 178 2-3-[(3,5Dibromo-4-hydroxyphenyl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-ylbenzonitrile 1793-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-2-oxo-6-indolinecarbonitrile 1803-[(3,5-Dibromo-4-hydroxyphenyl)methylidene]-5-(2-[3-(dimethylamino)propyl]amino-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one 1813-[(3,5-dibromo-4-hydroxyphenyl)methylidene]-2-oxo-N-(4-pyridinylmethyl)-1,2-dihydro-3H-indole-5-carboxamide

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid or by reacting the acid with a suitable organic orinorganic base. Representative salts include the following salts:Acetate, Aluminum, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate,Bitartrate, Borate, Bromide, Calcium, Calcium Edetate, Camsylate,Carbonate, Chloride, Chloroprocaine, Choline, Clavulanate, Citrate,Dibenzylethylenediamine, Diethanolamine, Dihydrochloride, Edetate,Edisylate, Estolate, Esylate, Ethylenediamine, Fumarate, Gluceptate,Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate,Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide,Isethionate, Lactate, Lithium, Lactobionate, Laurate, Malate, Maleate,Magnesium, Mandelate, Mesylate, Methylbromide, Methyinitrate,Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphateldiphosphate, Polygalacturonate, Potassium, Procaine,Salicyiate, Sodium, Stearate, Subacetate, Succinate, Sulfate, Tannate,Tartrate, Teoclate, Tosylate, Triethanolamine, Triethiodide,Trimethylammonium and Valerate.

Salts which are not pharmaceutically acceptable may be useful in thepreparation of compounds of formula (I) and these form a further aspectof the invention.

Also included within the scope of the invention are the individualisomers of the compounds represented by formula (I) above as well as anywholly or partially equilibrated mixtures thereof. The present inventionalso covers the individual isomers of the compounds represented by theformulas above as mixtures with isomers thereof in which one or morechiral centers are inverted.

For the following defined terms, these definitions shall be applied,unless a different definition is given in the claims or elsewhere inthis specification.

As used herein, the term “aliphatic” refers to the terms alkyl,alkyiene, alkenyl, alkenylene, alkynyl, and alkynylene.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having a specified number of carbon atoms, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Examples of “alkyl” as used herein include, but are not limitedto, n-butyl, n-pentyl, isobutyl, and isopropyl, and the like. The term“alkyl” as used herein also generically refers to the below-definedterms, “alkylene”, “alkenyl”, “alkenylene”, “alkynyl” and “alkynylene”.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

Examples of “alkylene” as used herein include, but are not limited to,methylene, ethylene, and the like.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon—carbon doublebond, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

As used herein, the term “alkenylene” refers to an straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon—carbon double bonds, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkenylene”as used herein include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, methylene-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon—carbon triplebond, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon—carbon triple bonds, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkynylene”as used herein include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, “cycloalkyl” refers to a alicyclic hydrocarbon groupwith one or more degrees of unsaturation, having from three to twelvecarbon atoms, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. “Cycloalkyl” includes by way of examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl, and the like. The term “cycloalkyl” as used herein alsogenerically refers to the below defined terms “cycloalkylene”,“cycloalkenyl”, and “cycloalkenylene”.

As used herein, the term “cycloalkylene” refers to an non-aromaticalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-11-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “cycloalkenyl” refers to a substitutedalicyclic hydrocarbon radical having from three to twelve carbon atomsand at least one carbon-carbon double bond in the ring system,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 1-cyclopentene-3-yl,1-cyclohexene-3-yl, 1-cycloheptene-4-yl, and the like.

As used herein, the term “cycloalkenylene” refers to a substitutedalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms and at least one carbon-carbon double bond in the ringsystem, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 4,5-cyclopentene-1,3-diyl,3,4-cyclohexene-1,1-diyl, and the like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered heterocyclic ring having one ormore degrees of unsaturation containing one or more heteroatomicsubstitutions selected from S, SO, SO₂, O, or N, optionally substitutedwith substituents selected from the group consisting of lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halogen, lowerperfluoroalkyl, or others as identified throughout this specificationand claims. multiple degrees of substitution being allowed. Such a ringmay be optionally fused to one or more of another “heterocyclic” ring(s)or cycloalkyl ring(s). Examples of “heterocyclic” include, but are notlimited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane,piperidine, pyrrolidine, morpholine, tetrahydrothiopyran,tetrahydrothiophene, and the like. A more comprehensive listing of suchrings is found in the Summary of the Invention. The term “heterocyclic”also generically refers to the below-defined term “heterocyclylene”.

As used herein, the term “heterocyclylene” refers to a three totwelve-membered heterocyclic ring diradical having one or more degreesof unsaturation containing one or more heteroatoms selected from S, SO,SO₂, O, or N, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, lower perfluoroalkyl, or others as identifiedthroughout this specification and claims, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more benzene rings or to one or more of another “heterocyclic” ringsor cycloalkyl rings. Examples of “heterocyclyiene” include, but are notlimited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,morpholine-2,4-diyl, and the like. A more comprehensive listing of suchrings is found in the Summary of the Invention.

As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkyisulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of aryl include, but are not limited to, phenyl,2-naphthyl, 1-naphthyl, biphenyl, and the like.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “arylene” include, but are not limited to,benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and thelike.

As used herein, the term “heteroaryl” refers to a five—to seven—memberedaromatic ring, or to a polycyclic heterocyclic aromatic ring, containingone or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides andsulfur monoxides and sulfur dioxides are permissible heteroaromaticsubstitutions, optionally substituted with substituents selected fromthe group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, tetrazolyl, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl,or others identified throughout this specification and claims, multipledegrees of substitution being allowed. For polycyclic aromatic ringsystems, one or more of the rings may contain one or more heteroatoms.Examples of “heteroaryl” used herein are furan, thiophene, pyrrole,imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole,oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine,pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole,and indazole, and the like. A more comprehensive listing of such ringsis found in the Summary of the Invention. The term “heteroaryl” alsogenerically refers to the below-defined term “heteroaryiene”.

As used herein, the term “heteroarylene” refers to a five—toseven—membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl,or aryl, multiple degrees of substitution being allowed. For polycyclicaromatic ring system diradicals, one or more of the rings may containone or more heteroatoms. Examples of “heteroarylene” used herein arefuran-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl, alkenyl or alkynyl.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl, alkenyl, or alkynyl.

As used herein, the term “alkenylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkenyl or alkynyl.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl, alkenyl or alkynyl.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is alkyl, alkenyl or alkynyl.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl.

As used herein, the term “carbamate” or “carbamoyl” refers to the groupR_(a)R_(b)NC(O)—, where R_(a) and R_(b) are hydrogen, alkyl, aryl,heterocyclyl or heteroaryl.

As used herein, the term “alkylcarbonyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, or heterocyclyl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both situationswhere the event has or has not occurred.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above-defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₃ and so forth.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the terms “biohydrolyzable carbamate”, “biohydrolyzablecarbonate” and “biohydrolyzable ureide” is a carbamate, carbonate orureide, respectively, of a drug substance (in this invention, a compoundof general formula (I) which either a) does not interfere with thebiological activity of the parent substance but confers on thatsubstance advantageous properties in vivo such as duration of action,onset of action, and the like, or b) is biologically inactive but isreadily converted in vivo by the subject to the biologically activeprinciple. The advantage is that, for example, the biohydrolyzablecarbamate is orally absorbed from the gut and is transformed to (I) inplasma. Many examples of such are known in the art, and include by wayof example carbamates of lower alkylamines, substitutedethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, polyether amines, and the like. An example ofsuch a biohydrolyzable carbamate applied to the general formula (I) isillustrated below in general formula (A):

Other examples of biohydrolyzable carbamates include those situations inwhich R⁸ is an OH moiety and said OH is conjugated with a carbamoylconjugate to yield a biohydrolyzable carbamate wherein said carbamoylconjugate is selected from the group consisting of diethylaminocarbonyl,N-(2-hydroxyethyl)aminocarbonyl, N,N,-bis(2-hydroxyethyl)aminocarbonyl,4-morpholinocarbonyl and 4-methyl-1-piperazinylcarbonyl.

As used herein, the term “biohydrolyzable ester” is an ester of a drugsubstance (in this invention, a compound of general formula (I) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable ester is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl esters, lower acyloxy-alkylesters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylacylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drugsubstance (in this invention, a compound of general formula (I) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable amide is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl amides, α-amino acid amides,alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides andbiohydrolyzable esters and biohydrolyzable carbamates, carbonates, andureides, and also encompasses a) compounds in which the biohydrolyzablefunctionality in such a prodrug is encompassed in the compound offormula (I): for example, the lactam formed by a carboxylic group in R¹and an amine in R², and b) compounds which may be oxidized or reducedbiologically at a given functional group to yield drug substances offormula (1). Examples of these functional groups are, but are notlimited to, 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine,1,4-cyclohexadiene, tert-butyl, and the like.

As used herein, the term “affinity reagent” is a group attached to thecompound of formula (I) which does not affect its in vitro biologicalactivity, allowing the compound to bind to a target, yet such a groupbinds strongly to a third component allowing a) characterization of thetarget as to localization within a cell or other organism component,perhaps by visualization by fluorescence or radiography, or b) facileseparation of the target from an unknown mixture of targets, whetherproteinaceous or not proteinaceous. An example of an affinity reagentaccording to b) would be biotin either directly attached to (I) orlinked with a spacer of one to 50 atoms selected from the groupconsisting of C, H, O, N, S, or P in any combination. An example of anaffinity reagent according to a) above would be fluorescein, eitherdirectly attached to (I) or linked with a spacer of one to 50 atomsselected from the group consisting of C, H, O, N, S, or P in anycombination.

The term “pharmacologically effective amount” shall mean that amount ofa drug or pharmaceutical agent that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by a researcher or clinician.

Whenever the terms “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall beinterpreted as including those limitations given above for “aliphatic”and “aryl”. Alkyl or cycloalkyl substituents shall be recognized asbeing functionally equivalent to those having one or more degrees ofunsaturation. Designated numbers of carbon atoms (e.g. C₁₋₁₀) shallrefer independently to the number of carbon atoms in an aliphatic orcycloaliphatic moiety or to the aliphatic portion of a largersubstituent.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “halogen” or “halo” shall include iodine,bromine, chlorine and fluorine.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent —COOH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “aminosulfonyl” shall refer to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” shall refer to the substituent—C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the substituent —S—.

As used herein, the term “sulfenyl” shall refer to the substituent—S(O)—.

As used herein, the term “sulfonyl” shall refer to the substituent—S(O)₂—.

Preparation

The compounds of formula (I) can be prepared readily according to thefollowing reaction Schemes (in which all variables are as definedbefore) and Examples or modifications thereof using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants which arethemselves known to those of ordinary skill in this art, but are notmentioned in greater detail.

The most preferred compounds of the invention are any or all of thosespecifically set forth in these examples. These compounds are not,however, to be construed as forming the only genus that is considered asthe invention, and any combination of the compounds or their moietiesmay itself form a genus. The following examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are degreesCelsius unless noted otherwise.

Abbreviations used in the Examples are as follows:

g=grams

mg=milligrams

L=liters

mL=milliliters

mL=microliters

M=molar

N=normal

mM=millimolar

i.v.=intravenous

p.o.=per oral

s.c.=subcutaneous

Hz=hertz

mol=moles

mmol=millimoles

mbar=millibar

psi=pounds per square inch

rt=room temperature

min=minutes

hr=hours

mp=melting point

TLC=thin layer chromatography

R_(f)=relative TLC mobility

MS=mass spectrometry

NMR=nuclear magnetic resonance spectroscopy

APCI=atmospheric pressure chemical ionization

ESI=electrospray ionization

m/z=mass to charge ratio

HPLC=high pressure liquid chromatography

t_(r)=retention time

Pd/C=palladium on activated carbon

ether=diethyl ether

MeOH=methanol

EtOAc=ethyl acetate

TEA=triethylamine

DIEA=diisopropylethylamine

THF=tetrahydrofuran

DMF=N, N-dimethylformamide

DMSO=dimethylsulfoxide

DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone

LAH=lithium aluminum hydride

TFA=trifluoroacetic acid

HCl=hydrochloric acid

LDA=lithium diisopropylamide

THP=tetrahydropyranyl

NMM=N-methylmorpholine, 4-methylmorpholine

HMPA=hexamethylphosphoric triamide

DMPU=1,3-dimethylpropylene urea

d=days

ppm=parts per million

kD=kiloDalton

LPS=lipopolysaccharide

PMA=phorbol myristate acetate

SPA=scintillation proximity assay

EDTA=ethylenediamine tetraacetic acid

FBS=fetal bovine serum

PBS=phosphate buffered saline solution

Several of the following examples represent single E isomers, single Zisomers and mixtures of E/Z isomers. Determination of the E and Zisomers can be done by analytical methods such as x-ray crystallography,¹H NMR and ¹³C NMR.

GENERAL REACTION SCHEMES

Compounds of the invention may be prepared by methods known in the art,where such a method is shown in Reaction Scheme 1.

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ are defined as in formula (I).

The conversion of II and III to I involves methods known as the aldolcondensation followed by elimination which is well described in“Advanced Organic Chemistry,” Carey and Sundberg, 3rd edition, PlenumPress, 1990, principally contained in chapter 2 of part B. The reactionmay be conducted using acid (for example concentrated HCI) incombination with a suitable solvent, such as acetic acid. Alternatively,catalytic acid conditions may be used such as using a catalytic amountof para-toluenesulfonic acid in a suitable solvent such as toluene.

Benzaldehydes of formula (II) are commercially available, or may beprepared by published procedures or variations of published procedures.Reaction Scheme 2 depicts two routes to readily synthesize substitutedbenzaldehydes that are not commercially available.

Generation of the substituted compounds of formula (II) may be obtainedby a variety of methods by those skilled in the art. For example, theconversion of (IV) to (II) may be conducted by treating (IV) in asuitable solvent such as acetic acid with hexamethylenetetramine at atemperature of 90° C. to 130° C. Alternatively, (V) can be converted to(II) by treating (V) in a suitable solvent such as dioxane with a smallamount of water with DDQ at a temperature of 0° C. to 140° C. Inaddition to the above, one compound of formula (II) can be converted toanother compound of formula (II) by a chemical transformation of theappropriate substituent or substituents. For example, when R⁸ ishydroxyl in (II), the conversion to a carbamate, carbonate, and ether isconducted by treating (II) in a suitable solvent such as THF with analkylating agent such as chloromethyl-R, or an acylating agent such asalkylchloroformates and alkylcarbamoylchlorides in a suitable solventsuch as dichloromethane.

Oxindoles of formula (III) are commercially available, or may beprepared by published procedures or variations of published procedures.Reaction Scheme 3 depicts several routes to synthesize compounds offormula (III).

R¹, R², R³, R⁴, are defined as in formula (I).

The aniline of formula (VI) can be converted to the isatin of formula(VII) utilizing a known transformation called the SandmeyerIsonitrosoacetanilide Isatin synthesis (T. Sandmeyer, Helv. Chim. Acta2, 234 (1919)) where (VI) may be condensed with chloral hydrate andhydroxylamine followed by cyclization with concentrated sulfuric acidand quantitative hydrolysis to a substituted isatin of formula (VIl) ondilution with water. The conversion of (VII) to (III) may be conductedutilizing a known transformation called the Wolf-Kishner Reduction bytreatment with hydrazine hydrate in a suitable solvent such as ethanolat a temperature of 20° C. to 80° C. to form (VIII). The conversion of(VIII) to (III) may be conducted by treatment with sodium ethoxide in asuitable solvent such as ethanol at a temperature of 0° C. to 80° C.

Alternatively, a substituted aniline of formula (VI) can be converted toa compound of formula (III) utilizing known chemistry. (P. G. Gassmanand T. J. van Bergen, Journal of the American Chemical Society, 1974,96(17), pages 5508-5512). The amine of formula (VI) may be converted toa compound of formula (XI) by treatment with t-butylhypochlorite,followed by treatment with ethyl methylthioacetate, followed bytreatment with triethylamine in a suitable solvent such as anhydrousdichloromethane at a temperature of 78° C to 22 ° C. The conversion of(XI) to (III) may be conducted by treatment of (XI) with W-2 RaneyNickel in a suitable solvent such as ethanol or treatment with asaturated solution of ammonium chloride followed by treatment withactivated zinc in a suitable solvent such as THF.

An indole of formula (IX) may be converted to (X) utilizing a methodwell described in the literature (A. Marfat and M. Carta, Tetrahedronletters, 28(35) pp 4027-4030, 1987) by treatment with pyridiniumperbromide in a suitable solvent such as t-butyl alcohol at atemperature of 25° C. A compound of formula (X) may be converted to(III) by treatment with 10% Pd/C in a suitable solvent such as anhydrousethanol at 30 to 50 psi of hydrogen or by treatment with a saturatedsolution of ammonium chloride followed by treatment with activated zincin a suitable solvent such as THF.

In addition to incorporating substitutions into the initial stages ofthe synthesis, one compound of formula (III) can be converted to anothercompound of formula (III) by a chemical transformation to theappropriate substituent or substituents. For example, Reaction Scheme 4demonstrates several well established transformations forfunctionalizing an oxindole of formula (III). Oxindole may be convertedto a sulfonic acid derivative (IIIa) by treatment of (II) withchlorosulfonic acid at a temperature of 0° C. to 60° C. A compound offormula (IIIa) may be converted to (IIIb) where R is substituted orunsubstituted amino, by treatment with a diverse set of amines. By wayof example, (IIIa) may be treated with ammonium hydroxide to provide asulfonamide derivative of formula (IIIb). Compound (III) may beconverted to (IIIc) by treatment with an acid chloride in the presenceof aluminum chloride in a suitable solvent such as dichloromethane orcarbon disulfide at a temperature of 0° C. to 45° C. When R is OH in(IIIc) which is synthesized according to scheme 3, the conversion ofcarboxylic acid (IIIc) to esters and amides of formula (IIId) involvesmethods known in peptide chemistry, for example the reaction my beconducted using HOBt in combination with a dehydrating agent such asdicyclohexylcarbodiimide in a suitable solvent such as DMF. (III) may beconverted to (IIIe) by treating (III) with chloroacetyl chloride in thepresence of aluminum chloride in a suitable solvent such asdichloromethane or carbon disulfide at a temperature of 0° C. to 45° C.Further functionalization to various heterocyclic groups may be achievedthrough treatment of (IIIe) with diversely substituted amidines,thioamides, ureas and substituted aminopyridines. For example, (IIIe)may be converted to (IIIf) by treating (IIIe) with thioacetamide in asuitable solvent such as acetic acid at a temperature of 22° C. to 100°C. Compounds of formula (IIIg), where R is, for example an alkyl orcyclic amine, may be obtained by treating (IIIe) with diversenucleophiles such as amines in a suitable solvent such as THF at atemperature of 22° C. to 80° C.

A chemical transformation of a halogenated oxindole of formula III toanother compound of formula III is described in Reaction Scheme 5. Forexample, a compound of formula (IIIh) where X is bromo or iodo may betreated with a tributyltin heterocycle, for example3-pyridyltributyltin, in the presence of a palladium catalyst, forexample bistriphenylphosphine dichloropalladium, in a suitable solvent,such as acetonitrile, to form (IIIj). Alternately, (IIIh) may beconverted to (IIIj) by treatment with a heterocyclic or aromatic boronicacid, for example thiophene-3-boronic acid, in the presence of base, forexample tetrakis-triphenyl phosphine palladium, in a suitable solvent,such as toluene, at a temperature of 22° C. to 125° C.

R¹, R², R³, R⁴, are defined as in formula (I).

A compound of formula (III) may also be synthesized using a methoddescribed by Reaction Scheme 6. A substituted 2-nitrotoluene (XII) maybe converted to a compound of formula (XIII) by treatment with diethyloxalate and sodium ethoxide in a suitable solvent such as ethanol. Theproduct of this reaction can be directly treated with water to form(XIII) which could be converted to a compound of formula (XIV) bytreatment with a hydrogen peroxide solution and sodium hydroxide inwater at temperatures between 0° C. and 100° C. Treatment of (XIV) withzinc in sulfuric acid and a suitable solvent such as ethanol can providea compound of formula (III). Alternately, a compound of formula XIV maybe synthesized from a compound of formula XV where X is a halogen.Compound XV may be treated with a solution containing diethyl malonateand sodium ethoxide in a suitable solvent such as, ethanol, at atemperature from 0° C. to 78° C. to provide a compound of formula XVI.This compound of formula XVI may be hydrolyzed and decarboxylated toprovide XIV using standard conditions such as treatment of XVI withaqueous sodium hydroxide, followed by the treatment of XVI with aqueoushydrochloric acid.

PHARMACEUTICAL FORMULATION AND DOSES

The compounds of the present invention can be administered in such oral(including buccal and sublingual) dosage forms as tablets, capsules(each including timed release and sustained release formulations),pills, powders, granules, elixirs, tinctures, suspensions, syrups andemulsions. Likewise, they may also be administered in nasal, ophthalmic,otic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscularinhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

A therapeutically effective amount of a compound or salt of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal or patient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant physician or veterinarian.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.1 to 300 mg/kg of body weight perday, and particularly 1 to 100 mg/kg of body weight per day. Oral dosageunits will generally be administered in the range of from 1 to about 250mg and more preferably from about 25 to 250 mg. The daily dosage for a70 kg mammal will generally be in the range of about 10 mg to 5 grams ofa compound of formula 1. An effective amount of a salt of the presentinvention may be determined as a proportion of the effective amount ofthe compound per se.

Topical application similarly may be once or more than once per daydepending upon the usual medical considerations. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily. Furthermore, preferred compounds for thepresent invention can be administered in intranasal form via topical useof suitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin that art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as “carrier” materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paRaffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidytcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with paimitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula(I) in combination with a pharmaceutically acceptable carrier.

Parenteral administration can be effected by utilizing liquid dosageunit forms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as aqueousoleaginous medium and sterilizing the suspension or solution.

Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservations and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher ester as forexample flavored aqueous solution, while elixirs are prepared throughmyristyl paimitate or mixtures thereof.

Topical formulations of the present invention may be presented as, forinstance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams. The formulations mayalso contain compatible conventional carriers, such as cream or ointmentbases and ethanol or oleyl alcohol for lotions. Such carriers may bepresent as from about 1% up to about 98% of the formulation. Moreusually they will form up to about 80% of the formulation.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetRafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

The preferred pharmaceutical compositions are those in a form suitablefor oral administration, such as tablets and liquids and the like andtopical formulations.

SYNTHESIS EXAMPLES

We now set forth a selected number of synthesis examples whichillustrate the techniques used to obtain the compounds of the invention.It is believed that one of ordinary skill in the art will, in view ofthe synthesis schemes set forth above, be able follow these proceduresor modify them accordingly without undue experimentation in order toobtain any of the substitutions disclosed above. The following examplesare illustrative embodiments of the invention, not limiting the scope ofthe invention in any way. Reagents are commercially available or areprepared according to procedures in the literature. Example numbersrefer to those compounds listed in the tables above. ¹H NMR spectra wereobtained on VARIAN Unity Plus NMR spectrophotometers at 300 or 400 Mhz.Mass spectra were obtained on Micromass Platform II mass spectrometersfrom Micromass Ltd. Altrincham, UK, using either Atmospheric ChemicalIonization (APCI) or Electrospray Ionization (ESI). Analytical thinlayer chromatography (TLC) was used to verify the purity of someintermediates which could not be isolated or which were too unstable forfull characterization, and to follow the progress of reactions. Unlessotherwise stated, this was done using silica gel (Merck Silica Gel 60F254). Unless otherwise stated, column chromatography for thepurification of some compounds, used Merck Silica gel 60 (230-400 mesh),and the stated solvent system under pressure.

EXAMPLE 1;3-(3,5-Dibromo-4-hydroxy-benzylidine)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 1a 5-cyano-3-methylthiooxindole

A solution of 4-cyanoaniline (5.0 g, 42 mmol) in dry dichloromethane(100 mL) under N₂ was cooled to about −78° C. To this stirred solutionwas added a solution of tert-butylhypochlorite (4.6 g, 42 mmol) in drydichloromethane (10 mL) over 5 min. and the resulting solution stirredfor 10 minutes. A solution of ethyl methylthioacetate (5.45 mL, 5.69 g,42 mmol) in dry dichloromethane (10 mL) was than added dropwise and themixture stirred for 1 hour. Triethylamine (5.9 mL, 4.28, 42 mmol) wasadded dropwise and the solution allowed to warm to room temperature over1 hour. The reaction solution was washed with water (3×20 mL) and brine(1×20 mL), dried over anhydrous MgSO₄ and the solvent evaporated undervacuum to leave an orange oil. This oil was dissolved in diethyl ether(100 mL) and 2N aqueous hydrochloric acid (5 mL) was added and themixture stirred vigorously at room temperature for 18 hours. Theresulting tan solid was collected by filtration and washed with diethylether and dried under vacuum to give 5-cyano-3-methylthiooxindole as awhite solid, (6.4 g, 76%). ¹H NMR (CDCl₃) δ9.04 (br s, 1H) 7.64 (s, 1H),7.57 (d, 1H, J=8.4 Hz), 6.99 (d, 1H, J=8.4 Hz), 4.28 (s, 1H), 2.04 (s,3H). MS (−ve ES) 203 (100), (M−H).

Example 1b 5-Cyanooxindole

A solution of 5-cyano-3-methylthiooxindole (6.0 g, 29 mmol) in THF (100mL) was stirred at room temperature and a saturated aqueous solution ofNH₄Cl (100 mL) added followed by activated zinc (25 g, 0.38 mol). Theresulting mixture was stirred for 18 hours. The mixture was filteredthrough a pad of diatomaceous earth and the pad washed with THF (20 mL).The organic phase was separated, dried over anhydrous MgSO₄ and thesolvent evaporated to leave a tan solid. Trituration of this solid withdiethyl ether gave 5-cyanooxindole a white solid, (4.1 g, 88%). ¹H NMR(DMSO-d6) δ7.63 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 6.93 (d, 1H, J=8.4 Hz),3.55 (s, 2H). MS (−ve ES) 157 (100), (M−H)

Example 13-(3,5-Dibromo-4-hydroxy-benzylidine)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

The title compound was synthesized in an identical manner to example 2except 5-cyano-oxindole was used in place of5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one hydrochloride. ¹H NMR(DMSO-d6) δ11.17 (s, 1H), 8.75 (s, 2H), 8.11 (s, 1H), 7.91 (s, 1H), 7.64(d, 1H, J=8.4 Hz), 6.96 (d, 1H), J=8.4 Hz). MS (AP−ve) 419 (20) (M−H).

Example 23-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one

Example 2a 5-(2-Chloro-acetyl)-1,3-dihydro-indol-2-one

The following reagents were combined in the order listed under nitrogenat room temperature: aluminum chloride (17 g, 0.130 moles), carbondisulfide (40 mL), chloroacetyl chloride (3.01 g, 0.027 moles), andoxindole (2.73 g, 0.021 moles). The reaction mixture was warmed toreflux and stirring continued at this temperature for 3 h. The reactionwas cooled to room temperature and the liquid was carefully decantedoff. Ice water was added dropwise to the remaining residue undernitrogen (slowly and carefully). Addition of water was ceased when atotal of 50 mL had been added and the reaction was stirred for 1 h atroom temperature. The tan solid was collected by filtration, washed 3times with water and dried in vacuo at 72° C. to give a light tan solid(3.4 g, 79% yield). ¹H NMR (DMSO-d6) δ3.62 (s, 2H); 5.15 (s, 2H); 6.96(d, 1H); 7.84 (s, 1H); 7.91 (d, 2H); 10.84 (bs, 1H). APCI-MS m/z 208(M−H).

Example 2b 5-(2-Methyl-thiazol4-yl)-1,3-dihydro-indol-2-onehydrochloride

Thioacetamide (90 mg, 1.2 mmol) was added to a slurry of5-(2-chloro-acetyl)-1,3-dihydro-indol-2-one (250 mg,1.2 mmol) in aceticacid (3 mL). The reaction temperature was increased to 80° C. andstirred at this temperature for 16 h. The reaction mixture was cooled toroom temperature and the resultant precipitate was collected byfiltration. The solid was washed with EtOAc (2×20 mL) and ether (2×20mL) and dried in vacuo to afford a cream colored solid (300 mg, 94%yield). ¹H NMR (DMSO-d6) δ2.74 (s, 3H); 3.58 (s, 2H); 6.87 (d, 1H); 7.79(m, 3H); 10.57 (s, 1H). APCI-MS (−ve) m/z 229 (M−H), APCI-MS (+ve) m/z231 (M+H).Analytical calculated for C₁₂H₁₀N₂OS.HCl: C, 54.02; H, 4.16;N, 10.50; S, 12.02. Found: C, 53.73; H, 4.16; N, 10.17; S, 11.63.

Example 23-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one

5-(2-Methyl-thiazol4-yl)-1,3-dihydro-indol-2-one hydrochloride (0.030 g,0.13 mmol) and 3,5-dibromo-4-hydroxy-benzaldehyde (0.037 g, 0.13 mmol)were combined and slurried in acetic acid (1.0 mL). Concentratedhydrochloric acid (0.25 mL) was added to the reaction mixture whichcaused the solids to dissolve. A yellow precipitate was collected byfiltration after the reaction stirred for 4 h. The solid was washed withEtOAc (2×20 mL) and ether (2×20 mL) and dried in vacuo to afford abright yellow solid (0.045 mg, 64% yield). ¹H NMR (DMSO-d6) δ2.80 (s,3H); 6.89 (d, 1H); 7.77 (s, 1H); 7.82 (d, 1H); 7.86 (s, 1H); 8.27 (s,1H); 8.87 (s, 2H); 10.82 (s, 1H). Electrospray MS m/z (−ve) 491.Analytical calculated for C₁₉H₁₂N₂O₂Br₂S.HCl: C, 43.17; H, 2.48; N,5.30. Found: C, 42.82; H, 2.66; N, 5.14.

Example 85-Benzoyl-3-(3-bromo-5-ethoxy4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

The title compound was synthesized in an identical manner to example 2except 5-benzoyl oxindole was used in place of5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one hydrochloride and3-bromo-5-ethoxy4-hydroxy-benzaldehyde was used in place of3,5-dibromo-4-hydroxy-benzaldehyde. ¹H NMR (DMSO-d6) δ1.38 (t, J=7 Hz,3H), 4.14 (q, J=7 Hz, 2H), 6.94 (d, J=8.2 Hz, 1H), 7.50-7.68 (m, 4H),7.69-7.72 (m, 2H), 7.90 (s, 1H), 8.14 (s, 1H), 8.34 (d, J=1.7 Hz, 1H),8.48 (d, J=1.7 Hz, 1H), 10.15 (s, 1H), 11.02 (s, 1H); APCI-MS: m/z 464(m−H)⁻. Anal. Calcd for C₂₄H₁₈NO₄Br: C, 62.08; H, 3.91; N, 3.02; Br,17.21. Found: C, 61.98; H, 3.88; N, 3.08; Br, 17.28.

Example 93-(3,5-Dichloro4-hydroxy-benzylidene)-5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one

Example 9a 5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one

Aluminum trichloride (10.7 g, 7.5 mmole) was placed in a round bottomflask under nitrogen at room temperature. Dimethylformamide (1.7 mL) wasadded dropwise, which produced an exothermic reaction. The reactionstood for 15 minutes before the addition of oxindole (1 g, 7.5 mmole)followed by 3-methyl-butanoyl chloride (0.96 g, 8 mmole). The reactionwas heated to 70° C. for 60 minutes. The reaction was poured ontocrushed ice (100 g) with concentrated hydrochloric acid added (10 mL).The aqueous layer was extracted with EtOAc (100 mL). The organic layerwas washed with a saturated NaCl (aqueous) solution, dried over MgSO₄.The volatiles were removed in vacuo to afford the desired compound (1.38g, 85%). ¹H NMR (DMSO-d₆): d 10.71 (s, 1H); 7.82 (d, J=8, 1H); 7.77 (s,1H); 6.86 (d, J=8, 1H); 3.51 (s, 2H); 2.76 (d, J=7, 2H); 2.13-2.05 (m,1H ); 0.88 (d, J=7, 6H) ESI-MS: m/z 216 (m−H)⁻.

Example 93-(3,5-Dichloro4-hydroxy-benzylidene)-5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one

The title compound was synthesized in an identical manner to example 2except 5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one was used in placeof 5-(2methyl-thiazol4-yl)- 1,3-dihydro-indol-2-one and3,5-dichloro-4-hydroxy-benzaldehyde was used in place of3,5-bromo-4-hydroxy-benzaldehyde. ¹H NMR (DMSO-d₆): δ11.05 (s, 1H);10.99 (s, 1H1); 8.63 (s, 1H); 8.28 (s, 1H); 7.92 (s, 1H); 7.85 (d,J=8.2, 1H); 7.77 (s, 1H); 6.89 (d, J=8.2, 1H); 2.84 (d, J=6.8, 2H);2.21-2.08 (m, 1H); 0.92 (d, J=6.8, 6H). ESI-MS: m/z 388 (m−H)⁻.

Example 245-Cyclopropanecarbonyl-3-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

Example 24a 5-Cyclopropanecarbonyl-1,3-dihydro-indol-2-one

This compound was prepared in an identical manner to example 9a exceptthat cyclopropane carbonyl chloride was used in place of3-methyl-butanoyl chloride. ¹H NMR (DMSO-d₆): δ10.73 (s, 1H); 7.93 (d,J=8.2, 1H); 7.85 (s, 1H); 6.88 (d, J=8.2, 1H); 3.53 (s, 2H); 2.79 (t,J=6.2, 1H); 0.94 (d, J=6.2, 4H) ESI-MS: m/z 200 (m−H)⁻.

Example 245-Cyclopropanecarbonyl-3-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

This compound was prepared in an identical manner to example 179 exceptthat 5-cyclopropanecarbonyl-1,3-dihydro-indol-2-one was used in place of6-cyano-1,3-dihydro-indol-2-one. ¹H NMR (DMSO-d₆): δ11.11 (s, 1H); 10.80(bs, 1H); 8.86 (s, 2H); 8.46 (s, 1H); 8.02-7.98 (m, 2H); 6.98 (d, J=8.1,1H); 3.0-2.9 (m, 1H); 1.05 (d, J=6, 4H) ESI-MS: m/z 462 (m−H)⁻.

Example 255-Aminomethyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

Example 25a 5-Aminomethyloxindole

A slurry of 5-cyanooxindole (1.0 g, 6.3 mmol) and 10 palladium on carbon(0.05 g) in glacial acetic acid (50 mL) at room temperature washydrogenated under 40 psi pressure for 24 hours. The catalyst wasremoved by filtration through a pad of diatomaceous earth and thesolvent evaporated from the filtrate to leave an orange oil of5-aminomethyloxindole as an acetate salt (1.16 g). ¹H NMR (DMSO-d6)δ7.21 (s, 1H), 7.14 (d, 1H, J=7.6 Hz), 6.75 (d, 1H, J=7.6 Hz), 3.74 (s,2H), 3.44 (s, 2H). MS (+ve ES) 146 (100), (M−NH₂).

Example 255-Aminomethyl-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

The title compound was synthesized in an identical manner to example 2except 5-aminomethyl-oxindole acetate was used in place of5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one hydrochloride. ¹H NMR(DMSO-d6) δ10.80 (s, 1H), 8.76 (s, 2H), 8.14 (br s, 3H), 7.71 (s, 1H),7.65 (s, 1H), 7.31 (d, 1H, J=7.6 Hz), 6.88 (d, 1H, J=7.6 Hz), 3.96 (brq, 2H, J=6 Hz). MS(AP+ve) 408 (100) (M−NH₂).

Example 1191-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro-pyrrolo[3,2-f]quinolin-2-one

Example 119a 2-Hydroxyimino-N-(6-quinolinyl)acetamide hydrochloride

To a stirred solution of 10.0 g (60.0 mmol) of chloral hydrate in 250 mLof water was added 70.0 g (220 mmol) of sodium sulfate decahydrate,followed by a solution of 11.8 g (170 mmol) of hydroxylaminehydrochloride in 100 mL of water. A solution of 7.8 g (54 mmol) of6-aminoquinoline in 200 mL of 1.0 N HCl was then added with stirring.The resulting suspension was warmed, and 400 mL of 95% EtOH was added todissolve the suspension. The solution was refluxed for 0.75 h and thencooled to ambient temperature. The solution was neutralized withaddition of solid sodium bicarbonate, and the resulting solid wascollected by vacuum filtration and air dried to afford 8.1 g (60%) of2-hydroxyimino-N-(6-quinolinyl)acetamide as a solid: ¹H NMR (DMSO-d₆):7.76 (s, 1H); 7.80 (dd, 1H, J=3.7, 8.4 Hz); 8.14 (s, 2H); 8.68 (s, 1H);8.77 (d, 1H, J=8.4 Hz); 9.02 (d, 1H, J=3.7 Hz); 10.73 (s, 1H); 12.34 (s,1H). Mass spectrum (negative ion chemical ionization): m/z=214 (60%).

Example 119b 3-H-Pyrrolo[3,2-f]quinoline-1,2-dione

2-Hydroxyimino-N-(6-quinolinyl)acetamide (7.00 g, 32.5 mmol) wascombined with 70 mL of concentrated sulfuric acid with stirring andheated to a reaction temperature of 120° C. for 20 min, followed by anhour at 95° C. The reaction was allowed to cool to room temperature andwas added dropwise to a mixture of 155 g (1.25 mole) of sodium carbonatemonohydrate and 200 g of ice. After the addition was complete, water(600 mL) was added gradually to the mixture with stirring until allinorganic white solid was dissolved. The aqueous mixture was neutralizedto pH 7 with 1 M hydrochloric acid and the product was collected byfiltration. The collected solid was added to 200 mL of water anddissolved by dropwise addition of 1 M hydrochloric acid to freeentrapped salts. The product was then precipitated by addition ofsaturated aqueous sodium bicarbonate to pH 7. The product was collectedby filtration and dried under vacuum at 55° C. to give 3.89 g (60%) of3-H-pyrrolo[3,2-f]quinoline-1,2-dione as a red-brown solid. Massspectrum (negative ion chemical ionization): m/z=197 (30%). NMR(DMSO-d₆): δ7.43 (d, 1H, J=8.8 Hz), 7.66 (dd, 1H, J=4.1, 8.4 Hz); 8.29(d, 1H, J=8.8 Hz); 8.72 (d, 1H, J=8.4 Hz); 8.82 (d, 1H, J=3.3 Hz); 11.2(s, 1H).

Example 119c 1-Hydrazono-1,3-dihydropyrrolo[3,2-f]quinoline-2-one

3-H-Pyrrolo[3,2-f]quinoline-1,2-dione (3.89 g, 19.6 mmol) was combinedwith 12.0 mL of anhydrous hydrazine and 10.25 mL of water and heated at100° C. under a condenser and nitrogen atmosphere, with stirring, for 1hr. The reaction occasionally foamed into the condenser and heat wasremoved as needed to allow foaming to subside. The reaction was cooledand poured into 200 mL of water. The product was collected by filtrationand dried under vacuum at 55° C. to give 2.86 g (69%) of1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinoline-2-one as a brown solid.Mass spectrum (positive ion electrospray): m/z=213. NMR (DMSO-d₆): δ7.37(d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H),8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H).

Example 119d 6-aminoquinoline-5-carboxylic acid hydrazide

1-Hydrazono-1,3-dihydro-pyrrolo[3,2-f]quinoline-2-one (1.07 g, 5.05mmol) was combined with 6.0 mL of anhydrous hydrazine and 5.0 mL ofwater in a 100 mL flask (oversize to allow for foaming) and heated atreflux (145° C. oil bath) under a condenser and nitrogen atmosphere,with stirring. After 4.5 hr, analytical HPLC showed that all of thehydrazone had been consumed. The reaction was cooled, diluted with 75 mLof water, and filtered to give 0.45 g (air dried) of6-aminoquinoline-5-carboxylic acid hydrazide as an olive brown solid.Mass spectrum (negative ion electrospray): m/z=215 (100%). NMR(DMSO-d₆): δ3.64 (s, 2H), 4.22 (s, 2H), 5.66 (s, 2H), 7.25 (d, 1H, J=9.1Hz), 7.34 (m, 1H), 7.65 (d, 1H, J=9 Hz), 8.34 (d, 1H, J=8.5 Hz), 8.50(s, 1H), 9.27 (s, 1H).

Example 119e 1,3-dihydro-pyrrolo[3,2-f]quinoline-2-one

6-Aminoquinoline-5-carboxylic acid hydrazide was dissolved in 10 mL of 2M hydrochloric acid and heated briefly on a hot plate. The reaction wasneutralized by gradual addition of solid sodium bicarbonate andfiltered. The collected product was dried under vacuum at 55° C. to give416 mg (45%) of 1,3-dihydro-pyrrolo[3,2-f]quinoline-2-one as a brownsolid. Mass spectrum (negative ion chemical ionization): m/z=183 (60%).¹H NMR (DMSO-d₆): δ3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd,J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70(dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H).

Example 1191-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro-pyrrolo[3,2-f]quinolin-2-one

1,3-Dihydro-pyrrolo[3,2-f]quinoline-2-one (552 mg, 3.00 mmol) wascombined with 855 mg (3.05 mmol) of 3,5-dibromo-4-hydroxybenzaldehyde(TCl Chemicals) in 6 mL of glacial acetic acid with 1 mL of concentratedhydrochloric acid. The reaction was stirred at 115° C. for 8 hr, cooledand filtered, washing with ethyl acetate, to give 1.32 g of1-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro-pyrrolo[3,2-f]quinolin-2-onehydrochloride as a brown solid which consisted of a 9/1 mixture of Z/Eisomers. Mass spectrum (negative ion chemical ionization): m/z=443(40%), 445 (100%), 447 (40%). ¹H NMR (DMSO-d₆): δ7.69 (d, J=8.8 Hz, 1H);7.93 (dd, J=8.7, 4.9 Hz, 1H); 8.24 (d, J=8.8 Hz, 1H); 8.27 (s, 1H); 8.80(s, 1H); 9.04 (d, J=4.7 Hz, 1H); 9.51 (d, J=8.6 Hz, 1H); 11.3 (s, 1H).

Example 1303-(3,5-Dinitro-4-hydroxy-benzylidene)-5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one

The title compound was synthesized in an identical manner to example 2except 3,5-dinitro-4-hydroxy-benzaldehyde was used in place of3,5-dibromo-4-hydroxy-benzaldehyde. ¹H NMR (DMSO-d6) δ2.79 (s, 3H); 6.90(d, 1H); 7.78 (s, 1H); 7.82 (d, 1H); 7.97 (s, 1H); 8.29 (s, 1H); 9.39(s, 2H); 10.80 (bs, 1H). MS (+ve ES) 425 (MH+).

Example 1336-Bromo-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

Example 133a 4-Bromo-2-nitrophenylpyruvic acid

Diethyl oxalate (29.2 g, 0.2 mol) and 4-bromo-2-nitrotoluene (21.6 g,0.1 mol, Lancaster) were poured into a cooled sodium ethoxide solution,prepared from sodium (4.6 g, 0.2 mol) and absolute ethanol (90 mL). Themixture was stirred overnight at room temperature and then refluxed for10 minutes at the end of the reaction. Water (30 mL) was added and thereaction refluxed for 2.5 h. The reaction mixture was cooled andconcentrated to remove excess ethanol. The precipitate was collected byfiltration, washed with ether and dried. The crude sodium salt wasdissolved in water and acidified with conc. HCl. The solid precipitatedand was collected by filtration. The crude product was recrystallizedfrom hexane and ethyl acetate to give 12.5 g (43%) as a featheryputty-colored solid; ¹H-NMR (CDCl₃): δ8.40 (d, 1H, J=1.9 Hz). 7,84 (dd,1H, J=8.0, 2.0 Hz), 7.30 (d, 1H, J=2 Hz) 4.65 (s, 2H).

Example 133b 4-bromo-2-nitrophenylacetic acid

A 30% hydrogen peroxide solution (4.95 mL, 0.04 mol) was added dropwiseto a solution of 4-bromo-2-nitrophenylpyruvic acid (0.04 mol) and sodiumhydroxide (5.3 g 0.1 mol) in water (175 mL) stirring at 0° C. Thereaction solution was stirred for 1 h at 5° C. and then acidified withdilute HCl. The yellow precipitate was filtered and the crude productrecrystallized from hexane and ethyl acetate to yield 8.4 g (75%) as alight beige solid; ¹H-NMR (DMSO-d6): δ12.67 (br s, 1H), 8.28 (d, J=2.0Hz), 7.97 (dd, 1H, J=9.0 Hz, 2.0 Hz), 7.55 (d, 1H, J=8.0 Hz 4.00 (s,3H). MS (−ve) m/z: 259 (M−H).

Example 133c 6-Bromooxindole

Zinc dust (8.5 g, 0.13 mol) was added slowly to a solution of4-bromo-2-nitrophenylacetic acid (8.4 g, 0.03 mol) in 50% sulfuric acid(200 mL) and absolute ethanol (300 mL) at 90° C. over 0.75 h. Themixture was heated at this temperature for 2 h with stirring. The excessethanol was removed by evaporation in vacuo and the mixture wasfiltered. The filtrate was extracted with diethyl ether. The combinedorganic portions were washed with saturated sodium bicarbonate,saturated sodium chloride, filtered with Whatman 1 PS Phase Separatorpaper and evaporated in vacuo to give 3.8 g (56%) a pale peach solid.¹H-NMR (DMSO-d6): δ10.57 (brs, 1H), 7.14 (m, 2H), 6.98 (s, 1H), 3.47 (s,2H).

Example 1336-Bromo-3-(3,5-dichloro-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

The title compound is synthesized in an identical manner to example 2except 6-bromo-oxindole was used in place of5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-one hydrochloride and3,5-dichloro-4-hydroxy-benzaldehyde was used in place of3,5-dibromo-4a-hydroxy-benzaldehyde. ¹H NMR (DMSO-d6) δ7.05 (s, 1H);7.12 (d, 1H); 7.43 (d, 1H); 7.56 (s, 1H); 7.76 (s, 2H); 10.78 (bs, 1H);10.91 (bs, 1H). Electrospray MS (−ve) 384.

Example 1383-(3,5-Dibromo-4-hydroxy-benzylidene)-5-pyrid-3-yl-1,3-dihydro-indol-2-one

Example 138a 5-pyrid-3-yl- 1,3-dihydro-indol-2-one

A mixture of 0.736 g (2 mmol) of 3-tributyltin pyridine, 0.259 g (1mmol) of 5-iodo-oxindole, 0.497 g (3 mmol) of tetraethyl ammoniumchloride, and 0.035 g (0.05 mmol) of bis(triphenylphospine) palladium(II) chloride in 4 ml of acetonitrile was heated to reflux for 24 hrs.After cooling to ambient temperature the mixture was diluted with 20 mlof CHCl₃ and 50 ml of 10% potassium fluoride solution (aq) was added.Filtered the mixture through a 1 inch pad of celite and separated thelayers. The organic layer was concentrated in vacuo, and the residue waschromatographed on silica gel (EtOAc/MeOH 5%) to afford5-pyrid-3-yl-1,3-dihydro-indol-2-one as white solid (0.033 g, 16%): ¹HNMR (DMSO-d₆): δ10.51 (s, 1H); 8.83 (d, J=2.2, 1H); 8.51 (dd, J₁=1.3,J₂=4.6, 1H); 8.02-7.97 (m, 1H); 7.59 (s, 1H); 7.54 (d, J=8.1, 1H); 7.44(dd, J₁=4.7, J₂=7.9, 1H); 6.93 (d, J=8.1, 1H); 3.55 (s, 2H). APCI-MS:m/z 211 (m+H)⁺.

Example 1383-(3,5-Dibromo-4-hydroxy-benzylidene)-5-pyrid-3-yl-1,3-dihydro-indol-2-one

The title compound was prepared in an identical manner to example 2except that 5-pyrid-3-yl-1,3-dihydro-indol-2-one was used in place of5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one. ¹H NMR (DMSO-d₆):δ10.93 (s, 1H); 9.13 (s, 1H); 8.81 (s, 2H); 8.8-8.7 (m, 1H); 8.6-8.5 (m,1H); 8.23 (s, 1H); 7.94 (s, 1H); 7.9-7.8 (m, 1H); 7.72 (d, J=8, 1H);7.02 (d, J=8, 1H). APCI-MS: m/z 471 (M−H)⁻.

Example 144 N[bis(2-Hydroxyethyl)]-carbamic acid 2,6dibromo-4-[5-(2-methyl-thiazol4-yl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-phenylester

3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-(2-methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one(0.50 g, 0.95 mmol) was slurried in 10 mL of anhydrous THF undernitrogen with 4A molecular sieves for 4 hrs. Diisopropylethylamine (0.33mL, 1.9 mmol) was added to give a yellow-orange solution. In a separateflask, 0.50 ml of a phosgene solution (1.9 M in toluene, 0.95 mmol) and5 mL of anhydrous THF was cooled in an ice bath under apressure-equalizing dropping funnel and nitrogen atmosphere. Theyellow-orange solution of the phenoxide anion was transferred to thedropping funnel via syringe, and the solution was added dropwise to thephosgene solution over 30 min. The reaction was allowed to warm to roomtemperature over 1 hr. The reaction was cooled again in an ice bath, anda solution of 135 mg (1.28 mmol) of diethanolamine and 0.165 mL ofdiisopropylethylamine (0.95 mmol) in 2 mL of anhydrous THF was added inone portion. The reaction was allowed to warm to room temperature andstir overnight. The orange reaction solution was diluted with 100 mL ofethyl acetate, washed with 50 mL of 0.2 M aqueous sodium bicarbonate,and dried over sodium sulfate. Evaporation of solvent gave 0.6 g of thecrude product as an orange solid. The product was purified bychromatography on silica gel using 1:1 hexane/ethyl acetate followed byethyl acetate to give 209 mg of3-(3,5-dibromo-4-hydroxy-benzylidene)-5-(2-methyl-thiazol4-yl)-1,3-dihydro-indol-2-oneas an orange solid. Mass spectrum (positive ion chemical ionization):m/z=644 (M+23) for ⁷⁹Br with isotope peaks.

NMR (DMSO-d₆): (mix of E/Z isomers in ˜2:1 ratio) δ2.70 and 2.76 (2s,3H); 3.47 (m, 2H); 3.62 (m, 4H); 3.8 (m, 2H); 4.88 (m, 1H); 4.96 (m,1H); 6.92 and 6.96 (2d, 1H, J=8 Hz); 7.62 (d, 1.3H, J=8 Hz); 7.76-7.96(m, 2H); 8.15-8.33 (m, 2H); 8.87 (s, 0.7H); 10.81 and 10.88 (2s, 1H).

Example 1473-(3,5-Dibromo-4-ethoxycarbonate-benzylidene)-2-oxo-2,3dihydro-5-chloro-1H-indole

A heterogeneous mixture of3-(3,5-dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-5-chloro-1H-indole(0.41 g, 1.0 mmol) in dry dichloromethane (15 mL) under nitrogen wastreated with diisopropylethylamine (0.70 mL, 4.0 mmol) at roomtemperature. To the resulting homogeneous solution was added ethylchloroformate (0.19 mL, 2.0 mmol) in a dropwise manner and the mixturestirred for three hours. The reaction was first washed with a saturatedsodium bicarbonate solution, then with a saturated ammonium chloridesolution. The organic layer was dried over magnesium sulfate, filteredand concentrated. The residue was dissolved in dichloromethane, cooledin an ice bath and the product was precipitated with hexanes. The solidswere collected on a filter, washed with hexanes and air-dried to providethe title compound (0.34 g, 68%). ¹H NMR (DMSO-d6): δ10.90 (s, 1H), 8.12(s, 2H), 7.70 (s, 1H), 7.35-7.40 (m, 2H), 6.96 (d, 1H), 4.43 (q, 2H),1.40 (t, 3H). Anal. Cald for C₁₈H₁₂NO₄Br₂Cl: C, 43.11; H 2.41; N, 2.79.Found: C, 43.01; H, 2.47; N, 2.73. MS (API+): 502(5) (M+1).

Example 1503-(3,5-Dibromo-4-pivaloyloxymethoxy-benzylidene)-2-oxo-2,3-dihydro-5-chloro-1H-indole

A solution of3-(3,5-dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-5-chloro-1H-indole (0.43 g, 1.0 mmol) in dry acetonitrile (20 mL) under nitrogenwas treated with potassium tert-butoxide (0.12 g, 1.1 mmol) at roomtemperature. The resulting orange heterogenous mixture was treated with18-crown-6 (0.053 g, 0.20 mmol) and stirred for 15 minutes before addingchloromethylpivalate (0.40 mL, 2.8 mmol). The reaction was heated toseventy degrees celsius, stirred for three hours then filtered whilehot. The filtrate was allowed to cool to room temperature and stirredovernight. The resulting solids were collected on a filter, washed withacetonitrile and dried under vacuum to provide the title compound (0.24g, 44%) as a mixture of E/Z isomers. ¹H NMR (DMSO-d6): (mixture of E/Zisomers) δ10.93 (s, 1H), 10.87(s, 1H), 8.85 (s, 2H), 8.09 (s, 2H), 7.94(s, 1H), 7.84 (d, 1H), 7.67 (s, 1H), 7.32-7.39 (m, 3H), 6.96 (d, 1H),6.91 (d, 1H), 5.91 (s, 2H), 5.88 (s, 2H), 1.23 (s, 9H), 1.22 (s, 9H). MS(ES-): 542 (60) (M−1). Anal. Calcd for C₂₁H₁₈NO₄ClBr₂: C, 46.40; H,3.34; N, 2.58. Found: C, 46.33; H, 3.30; N, 2.55.

Example 152 2,6-Dibromo-4-[(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]phenyl N-[2-(2-hydroxyethoxy)ethyl]carbamate

To a solution of3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-iodo-1,3-dihydro-indol-2-one(210 mg, 0.40 mmol) in 20 ml of THF under nitrogen was added 1Mpotassium t-butoxide in THF (0.40 ml, 0.40 mmol) dropwise via syringe.The solution was cooled to 0° C. and 1.97M phosgene in toluene (0.21 ml,0.41 mmol) was added dropwise via syringe and the reaction mixture wasstirred 10 minutes. 2-(2-Aminoethoxy)ethanol (40 μl, 0.40 mmol) was thenadded via syringe followed by N-methyl morpholine (˜45 mg, ˜45 mmol).The reaction mixture was stirred 10 minutes at 0° C. and then allowed towarm to room temperature. The solution was diluted with an equal volumeof ether, filtered through a fine frit to clarify, and further dilutedwith 10 ml of ether. The product was then precipitated by the additionof ˜80 ml of hexanes and was filtered and washed with more hexanes togive 0.21 g (79%) of the title compound as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) 6: 10.77 (s, 1H), 8.24 (t, J=5.6 Hz, 1H), 8.02 (s, 2H),7.6 (s, 1H), 7.57 (s, 1H), 7.55 (dd, J=8.2, 1.6 Hz, 1H), 6.71 (d, J=8.2Hz, 1H), 4.58 (br t, 1H), 3.52-3.42 (m, 6H), 3.27-3.20 (m, 2H). ESI-MSm/z 673, 675, 677 (M+23). Anal. Calcd. for C₂₀H₁₇Br₂IN₂O₅: C, 36.84; H,2.63; N, 4.30. Found: C, 36.75; H, 2.60; N, 4.22.

Example 1563-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylicacid

3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylicacid was prepared from 5-carboxylic acid oxindole and3,5-dibromo-4-hydroxybenzaldehyde following the identical procedure asin example 2 except3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylicacid was used in place of5-(2-Methyl-thiazol-4-yl)-1,3-dihydro-indol-2-one hydrochloride. Yield79%. ¹H-NMR (DMSO-d6): δ12.6 (bs, 1H), 10.96 (s, 1H), 10.61 (bs, 1H),8.17 (s, 1H), 7.93 (s, 2H), 7.84 (d, J=8.2 Hz, 1H), 7.54 (s, 1H), 6.93(d, J=8.2 Hz, 1H). Mass spectrum (negative ion APCI): m/z=436 (M−1, 5%),438 (M−1, 10%), 440 (M−1, 8%).

Example 159N[3-(3,5-Dibromo-4-hydroxy-benzylidine)]-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide

Example 159a 5-nitro-1,3-dihydro-indol-2-one

A solution of 5 g (37.6 mmol) of oxindole in 75 ml of conc. H₂SO₄ waschilled to −5° C. in an ice/EtOH bath. A solution of 3.83 g (45.1 mmol)of NaNO₃ in 25 ml of conc. H₂SO₄ was added dropwise over 30 min. Themixture was stirred at −5° C. for 1 hr. The ice bath was then removedand the mixture was allowed to slowly warm to ambient temperature. Themixture was poured onto 500 g of crushed ice. The solid was collected byvacuum filtration and air-dried. The solid was stirred in warm methanoland collected by vacuum filtration to yield5-nitro-1,3-dihydro-indol-2-one (1.7 g, 25%): ¹H NMR (DMSO-d₆): δ3.6 (s,2H), 6.95 (d, J=8.5 Hz, 1H), 8.1 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 11.01(s, 1H). APCI-MS: m/z 177 (m−H)⁻.

Example 159b 5-amino 1,3-dihydro-indol-2-one

A mixture of 1.5 g (8.4 mmol) of 5-nitro-1,3-dihydro-indol-2-one, 150 mgof Pd/C 10%, and 50 ml MeOH in 100 ml of EtOAc was placed on Parr®hydrogenator and charged with 45 psi of Hydrogen gas. The mixture wasshaken for 2 hrs. The mixture was filtered and the solvent was removedin vacuo to yield 5-amino 1,3-dihydro-indol-2-one (1.22 g, 98%): ¹H NMR(DMSO-d₆): δ3.27 (s, 2H), 4.6 (s, 2H), 6.34 (dd, J₁=2 Hz, J₂=8.1 Hz,1H), 6.45 (m, 2H), 9.88 (s, 1 H). APCI-MS: m/z 147 (m−H)⁻.

Example 159c N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide

A mixture of 200 mg (1.35 mmol) of 5-amino 1,3-dihydro-indol-2-one in 6ml of acetic anhydride was refluxed for 30 minutes. The reaction mixturewas poured onto 50 g of crushed ice. The mixture was stirred well andthe solid was collected by vacuum filtration. The solid was washed with200 ml of H₂O and air dried to yieldN-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (119 mg, 46%): ¹H NMR(DMSO-d₆): δ1.97 (s, 3H), 3.41 (s, 2H), 6.68 (d, J=8.4 Hz, 1H), ), 7.26(dd, J₁=2 Hz, J₂=8.4 Hz, 1H), 7.46 (d, J=2 Hz, 1H), 9.73 (s, 1H). 10.23(s, 1H),

ESI-MS: m/z 189 (m−H)⁻.

N[3-(3,5-Dibromo-4-hydroxy-benzylidine)]-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide.

A mixture of 0.050 g (0.26 mmol) ofN-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide and 0.081 g (0.29 mmol) of3,5-dibromo-4-hydroxybenzaldehyde was stirred in 2 ml of HOAc. 100 ?I ofconcentrated HCl was added and the mixture was heated to 80^(?) C. for 3hrs. After cooling to ambient temperature, the solid was collected byvacuum filtration and washed with EtOAc and Et₂O and dried in a vacuumoven to yieldN-[3-(3,5-dibromo-4-hydroxy-benzylidine)]-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamideas a yellow solid (0.76 g, 65%): ¹H NMR (DMSO-d₆): δ1.99 (s, 3H), 6.72(d, J=8.3 Hz, 1H), 7.17 (dd, J₁=1.8 Hz, J₂=8.3 Hz, 1H), 7.54 (s, 1H),7.86 (d, J=1.5 Hz, 1H), 8.79 (s, 2H), 9.74 (s, 1H), 10.54(s, 1H).APCI-MS: m/z 475 (m+Na)⁺

Example 1723-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylicacid (2-hydroxyethyl)amide

Example 172a 5-Carboxylic acid-1,3-dihydro-indol-2-one

5-Carboxylic acid-1,3-dihydro-indol-2-one methyl ester (5.6 g, 29.3mmol) was dissolved in hot acetonitrile (500 mL) and aluminium iodide(25 g, 61.3 mmol) added slowly. Reaction refluxed for 0.5 h and thenpoured onto ice-water and extracted twice with ethyl actetate (200 mL).Material insoluble in both phases was filtered off and washed withaqueous sodium thiosulfate solution, followed by water and dried. Yieldof 5-Carboxylic acid-1,3-dihydro-indol-2-one: 1.9 g. The ethyl acetatesolution was washed with aqueous sodium thiosulfate solution andconcentrated to dryness. Yield of 5-Carboxylicacid-1,3-dihydro-indol-2-one: 0.2 g. The aqueous phase was treated withsodium thiosulfate solution and on standing deposited more product as aprecipitate. This was filtered off, washed with water and dried. Yieldof 5-Carboxylic acid-1,3-dihydro-indol-2-one: 2.8 g; ¹H-NMR (DMSO-d6):δ12.60 (bs, 1H), 10.73 (bs, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.77 (s, 1H),6.90 (d, J=8.1 Hz, 1H), 3.56 (s, 2H). Mass spectrum (negative ionelectrospray): m/z=176 (M−1, 6%).

Example 1723-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylicacid (2-hydroxyethyl)amide

3-(3,5-Dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylicacid (0.34 9, 0.77 mmol) (Example 156) and ethanofamine (0.08 g, 1.3mmol) were dissolved in DMF (2 mL) and cooled with stirring to 5° C.Diethyl cyanophosphonate (0.172 g, 1 mmol), followed by triethylamine(0.25 g, 2.5 mmol) were added and stirring continued for 0.5 h at 50° C.and then the reaction allowed to warm to room temperature. After 1.5 hthe reaction was quenched with water (10 mL) and extracted four timeswith a 4/1 mixture of chloroform/isopropanol (25 mL). The organic phaseswere combined, dried over magnesium sulfate and concentrated to dryness.Recrystalization from ethanol gave 22 mg of3-(3,5-dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-5-carboxylicacid (2-hydroxyethyl)amide; ¹H-NMR (DMSO-d6): δ10.9 (s, 1H), 10. 7 (bs,1H), 8.81 (s, 2H), 8.25 (t, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.77 (s, 1H),7.72 (d, J=8.0 Hz, 1 H), 6.86 (d, J=8.0 Hz, 1 H), 4.73 (bs, 1H), 3.52(m, 2H), 3.37 (m, 2H). Mass spectrum (negative ion electrospray):m/z=479 (M−1, 22%), 481 (M−1, 35%), 483 (M−1, 30%).

Example 1796-Cyano-3-(3,5-dibromo-4-hydroxy-benzylidlene)-1,3-dihydro-indol-2-one

Example 179a 6-cyano-1,3-dihydro-indol-2-one

6-Bromo-1,3-dihydro-indol-2-one (0.621 g, 2.93 mmol), tributyltincyanide 1.11 g, 3.5 mmol), tetraammonium chloride hydrate (0.97 g, 5.9mmol), dichlorobis(triphenylphosphine)palladium(II) (0.21 g, 0.3 mmol)and tetrakis (triphenylphosphine)palladium(0) (0.342 g, 0.3 mmol) weretreated with dichloroethane (100 mL) and the reaction refluxed for 16 hunder nitrogen with stirring. A further addition of tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol) was made and refluxcontinued a further 6 h. A third addition of tetrakis(triphenylphosphine)palladium(0) (0.345 9, 0.3 mmol) was made and thereaction returned to reflux for 16 h. On cooling the reaction solutionwas washed twice with an aqueous solution of potassium fluoride (50 mL)and the organic phase dried over magnesium sulfate, filtered andevaporated to dryness. The product was subjected to chromatography onsilica gel using dichloromethane to give 140 mg of6-cyano-1,3-dihydro-indol-2-one contaminated with triphenylphosphineoxide. A second chromatographic purification chromatography on silicagel using dichloromethane gave 61 mg of pure6-cyano-1,3-dihydro-indol-2-one; ¹H-NMR (DMSO-d6): δ10.64 (bs, 1H), 7.37(s, 2H), 7.10 (s, 1H), 3.56 (s, 2H). Mass spectrum (negative ionelectrospray): m/z=157 (M−1, 100%).

Example 1796-Cyano-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one

6-cyano-1,3-dihydro-indol-2-one (46.3 mg, 0.29 mmol) and3,5-dibromo-4-hydroxybenzaldehyde (80 mg, 0.39 mmol) andp-toluenesulfonic acid monohydrate (1 mg, 0.005 mmol) were treated withtoluene (30 mL) and the reaction refluxed with stirring with aDean-Stark water trap attached for 1.5 h. During this time an orangesolid deposited, which, on cooling, was filtered off, washed withtoluene and dried in vacuo at 125° C. for 3 days to give 80 mg of6-cyano-3-(3,5-dibromo-4-hydroxy-benzylidene)-1,3-dihydro-indol-2-one;¹H-NMR (DMSO-d6): δ11.05 (bs, 1H), 8.86 (s, 2H), 7.97 (s, 1H), 7.85 (d,J=7.9 Hz, 1 H), 7.50 (d, J=7.9 Hz, 1 H), 7.20 (s, 1H). Mass spectrum(negative ion electrospray): m/z=417 (M−1, 48%), 419 (M−1, 100%), 421(M−1, 48%).

UTILITY

Kinase signal transduction results, in, among other responses, cellproliferation, differentiation and metabolism. Abnormal cellproliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,leukemia, glioblastoma, hemangioma; psoriasis, arteriosclerosis,arthritis and diabetic retinopathy or other disorders related touncontrolled angiogenesis and or vasculogenesis.

The efficacy of compounds of the present invention as inhibitors of Rafkinase activity can be evaluated and measured using pharmacologicalmethods known in the art or as described in detail below based onsimilarly established methodologies.

The potency of cRaf1 dependent kinase activity was measured using one oftwo assay formats. The first measured cRaf1 catalyzed phosphorylation ofMEK1, the natural substrate for cRaf1. This assay is referred to as thecRaf1 assay. The second measured the ability of cRaf1 to phosphorylateand activate MEK1. This assay is referred to as the Raf/MEK cascadeassay. The Raf/MEK cascade assay format was employed as the primaryscreen, since a greater signal was achieved with less enzyme. The cRaf1assay format was used to confirm that cRaf1 was the enzyme affected bythe compounds of the present invention.

A. cRaf1 Assay

Human cRaf1 tagged with poly histidine at the carboxyterminus wasexpressed in a baculovirus expression system and purfied by Ni chelateaffinity chromatography. Human MEK1 was expressed in E. coli as a fusionprotein with Glutathione-S-transferase, and purified by glutathionesepharose affinity chromatography. Typically assays were performed in afinal volume of 40-100 mL with and without inhibitors. Reactionscontained cRaf1 (20 nM), MEK1 (100-500 nM), [γ-³²P]ATP (10-20 mM), Mg²⁺(10 mM), MOPS (50 mM, pH 7.5). Reactions were incubated at roomtemperature for periods of time ranging from 20-120 minutes. Inhibitorswere diluted in 100% DMSO prior to addition to the assay. Reactions wereterminated with an equal volume of 0.5% phosphoric acid. MEK1phosphorylation was detected by scintillation counting followingcollection of protein onto phosphocellulose filters.

B. Raf/MEK Cascade Assay

Human cRaf1 and MEK1 were purified as described above. A peptidesubstrate phosphorylated by MEK1 was used as the final phosphoryl groupacceptor. The sequence of the peptide HTGFLTEYVATRWKK-OH was derivedfrom the site in ERK2 that is phosphorylated by MEK1. Assay conditionswere the same as those described above except for the followingmodifications. Reactions contained cRaf1 (1-5 nM), MEK1 (60 nM), andpeptide (250 mM).

C. CDK1 and CDK2

Cyclin dependent protein kinase assays utilized the peptidesBiotin-aminohexyl-AAKAKKTPKKAKK and Biotin-aminohexyl-ARRPMSPKKKA-NH₂ asphosphoryl group acceptors. CDK1 and CDK2 were both expressed utilizinga baculovirus expression system and were partially purified to comprise20-80% of total protein, with no detectable competing reactions present.Typically, assays were performed by incubating either enzyme (0.2-10nM), with and without inhibitor, one of the two peptide substrates (1-10uM), [γ-³²P]ATP (1-20 uM), and 10-20 mM Mg²⁺ for periods of timegenerally within the range 10-120 minutes. Reactions were terminatedwith 0.2-2 volumes of either 20% acetic acid or 50-100 mM EDTA bufferedto pH 7 (substrate consumption<20%). The buffer employed in enzymeassays was either 30 mM HEPES 7.4 containing 0.15M NaCl and 5% DMSO, thebuffer 50 mM MOPS 7.0 containing 0.15M NaCl and 5% DMSO, or the buffer100 mM HEPES pH 7.5 containing 0.1 mg/mL BSA and 5% DMSO. Inhibitorswere diluted in 100% DMSO prior to addition into the assay. Detection ofpeptide phosphorylation was accomplished by scintillation countingfollowing either collection of peptide onto phosphocellulose filters(for reactions stopped with acetic acid), collection of peptide in wellsof 96 well plates coated with Streptavidin (Pierce) (reactions werestopped with EDTA), or addition of Avidin coated Scintillant impregnatedbeads (Scintillation Proximity Assays from Amersham, reactions werestopped with EDTA). Counts detected by any of these methodologies minusthe appropriate background (assays with additional 40 mM EDTA or lackingpeptide substrate) were assumed to be proportional to the reactioninitial rates, and IC50s were determined by a least squares fit to theequation CPM=V_(max)*(1-([I]/(K+[I])))+nsb, or −pIC50s were determinedby a fit to the equation CPM=nsb+(V_(max)−nsb)/(1+(x/10^(x)−pIC50)),where nsb are the background counts.

D. UL97

UL97 was produced as a GST fusion protein from a baculovirus vectorexpressed in sf9 cells as described by He (He et al., 1997). UL97 wasassayed as a protein kinase using ³²p transfer from ATP to histone H2Bwith detection of radiolabeled histone bound to phosphocellulose. Assaymixes for testing inhibitors of UL97 activity contained 2 mM [γ³²P]-ATP,15 mM histone H2B, 50 mM sodiumCHES, pH 9.5, 1 M NaCl, 2 mMdithiothreitol and 10 mM MgCl₂. Inhibitors were dissolved in dilutedDMSO to give a final DMSO concentration in the reaction of 1% DMSO.After incubation at 20° C., the reactions were terminated by addition of10 volumes of 75 mM phosphoric acid, 30 mM ATP, 1 mM EDTA, then werespotted onto phosphocellulose filters and washed four times with 75 mMphosphoric acid. Radioactivity was determined by liquid scintillationcounting.

E. SRC/lck Enzyme Assay

The peptide substrates used in Src and Lck assays were biotin-aminohexylEEIYGEF-NH₂ (Src) and biotin-aminohexyl-EAIYGVLFAKKK-NH₂ (Lck). The srcand lck proteins were purified to homogeneity from a baculovirusexpression system and preactivated before adding to assay mixtures. Themaximum activation was achieved by incubating concentrated enzyme (10-30uM) on ice for 40 min in the presence of 1 uM ATP and 10 mM MgCl₂ in 100mM HEPES, pH 7.5. The activated enzyme was diluted to 2 nM into an 50 mLreaction mixture containing 100 mM HEPES, pH 7.5, 5 uM ATP, 10 mM MgCl₂,2 uM peptide, 0.05 mg/mL BSA, and an inhibitor at varying concentrationsand with or without 8 mCi/mL [γ-³³P]ATP dependent upon the method ofanalysis for the extent of reaction. The controls were reactions in thepresence (negative controls) or absence (positive controls) of 50 mMEDTA. Reactions were allowed to proceed for 30 min at room temperatureand quenched with addition of EDTA to 50 mM in 220 uL. The extent ofreactions was analyzed in one of the two ways: an Elisa-based and aradioactive isotope-based. The quenched samples (200 uL) weretransferred to a neutravidin coated plate (Perice) and incubated at roomtemperature for 40 min to allow biotinylated peptide to bind toneutravidin. The unbound peptide and the rest of the solution was washedaway using a plate washer. In the Elisa format, a 200 uL HRP-PY20 antiphosphotyrosine antibody conjugate solution was added. After incubationfor about 30 min, the plated was washed to remove unbound antibody-HRPconjugate. An Elisa substrate, K-blue (Neogen), was added and the Elisareaction quenched with Red-stop (Neogen) after 15 min. The plate wasread at Ar25 in a plate reader. In the isotope-based format, thereactions had been performed in the presence of [γ-³³P]ATP. 200 mLScintiverce DB was added to each well of the plate with boundbiotin-peptide. The plate was sealed and counted in a micro-b-counter(Wallac). IC₅₀ values were obtained by fitting raw data to A₆₂₅(cpm)=V_(max)*(1-([I]/(IC₅₀+[I])))+b, where b is background.

F. VEGFR-2

The peptide substrate used in the VEGFR-2 assay wasbiotin-aminohexyl-EEEEYFELVAKKKK-NH₂. The kinase domain of the enzymewas purified to homogeneity from a baculovirus expression system. Theactivated enzyme was diluted to 0.4 nM into a 60 μl reaction containing100 mM HEPES, pH 7.5, 5 μM ATP, 10 mM MgCl₂, 5 μM peptide, 0.1 mM DTT,0.05 mg/ml BSA, and an inhibitor at varying concentrations. The controlswere reactions in the presence (negative controls) or absence (positivecontrols) of 50 mM EDTA. Reactions were incubated for 30 min at roomtemperature, and then quenched by the addition of EDTA to 60 mM in 210μl. The quenched samples (190 μl) were transferred to aneutravidin-coated plate (Pierce) and incubated at room temperature for40 min to allow biotinylated peptide to bind to the neutravidin. Theunbound components of the reaction were removed by washing with a platewasher, then 200 μl HRP-PY20 anti-phosphotyrosine antibody conjugate wasadded to each well. After incubation for 40 minutes, the plate waswashed to remove any unbound anitbody.

A HRP substrate, K-blue (Neogen) was added and the reaction was quenchedwith Red Stop (Neogen) after 20 min. The absorbance of the wells wasread at A₆₅₀ in a plate reader.

IC₅₀ values were obtained by fitting raw data toA₆₅₀=V_(MAX)*(1-[I]/IC₅₀+[I])))+b, where b is background.

Representative data are summarized in Table 3. Table 3 illustrates theinhibitory activity of compounds of the present invention against arepresentative kinase (raf).

TABLE 3 Raf Kinase Example activity 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 +10 + 11 + 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 + 23 +24 + 25 ++ 26 + 27 + 28 ++ 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 +38 + 39 + 40 + 41 + 42 + 43 + 44 + 45 + 46 + 47 ++ 48 ++ 49 ++ 50 ++51 + 52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64 +65 + 66 + 67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 +79 + 80 +++ 81 + 82 + 83 + 84 + 85 + 86 + 87 +++ 88 + 89 + 90 + 91 +92 + 93 + 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 ++ 102 ++ 103 +++104 + 105 + 106 +++ 107 + 108 + 109 + 110 + 111 + 112 ++ 113 ++ 114 +115 + 116 + 117 +++ 118 + 119 + 120 + 121 + 122 + 123 + 124 + 125 +126 + 127 + 128 + 129 + 130 + 131 ++ 132 + 133 + 134 + 135 + 136 + 137 +138 + 139 + 140 + 141 + 142 + 143 + 144 +++ 145 + 146 +++ 147 +++ 148+++ 149 +++ 150 +++ 151 +++ 152 + 153 +++ 154 +++ 155 +++ 156 + 157 +158 + 159 + 160 + 161 + 162 + 163 + 164 ++ 165 + 166 + 167 +++ 168 +169 + 170 + 171 + 172 + 173 + 174 + 175 + 176 + 177 + 178 + 179 + 180 +181 + Key: Range Symbol <0.010-1.00 μM + 1.00-10.00 μM ++ 10.00-100 μM+++

Cell Based Efficacy (MTT Assay)

The potency of compounds of the invention are tested for their abilityto inhibit cell proliferation and cell viability. The metabolicconversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT, Sigma #M2128) to a reduced form is a commonly used measureof cellular viability. Following is the procedure:

Cells are maintained in 75 cm² tissue culture flasks until ready foruse. The cells are grown and plated for the assay in Dulbecco's modifiedEagle's media containing 10% fetal bovine serum. For example, thefollowing cell lines can be used: a) human foreskin fibroblasts (HFF),b) HT29 (human colon carcinoma cell line), c) MDA-MB-468 (human breastcarcinoma cell line), d) RKO (human colon adenocarcinoma cell line), e)SW620 (human colon carcinoma cell line), f) A549 (human lung carcinomacell line), and g) MIA PACA (human pancreatic carcinoma cell line).Cells are maintained at 37° C. in 10% CO₂, 90% humidified air. Cells areplated in 96-well tissue culture plates at the densities listed below.100 μL of cell suspension is added to each well of the 96-well plateexcept the top row of the plate which contains no cells and serves as areference for the spectrophotometer.

Cell line Density HFF 2500 cells/well HT29 cell lines 2500 cells/wellMDA-MB-468 cell line 5000 cells/well SW620 4000 cells/well MIA PACA 3000cells/well PC-3 4500 cells/well

Cells are incubated overnight in Dulbecco's modified Eagle's mediacontaining 10% fetal bovine serum at 37° C. in 10% CO₂, 90% humidifiedair prior to dosing. Cells are dosed in 10 sequential 3-fold dilutionsstarting at 30 uM depending upon the solubility of the compound.Compounds with solubilities of less than 30 uM are dosed at the highestsoluble concentration. Stock solutions of compounds are made in 100%dimethyl sulfoxide (DMSO). Stock solutions are diluted in Dulbecco'smodified Eagle's media containing 100 ug/mL gentamicin and 0.3 to 0.6%DMSO at the twice the highest concentration to be placed on the cells.If compounds have been dissolved in DMSO the final concentration of DMSOon the cells is kept below 0.3%. 3-fold serial dilutions are performedon each compound to prepare 10 concentrations of the compound fordosing. 100 μL of diluted compound is added to the 100 μL of mediacurrently on the dish. For each concentration of compound, 2-4 replicatewells are prepared.

Cells are returned to incubator and allowed to proliferate in thepresence of compound for 72 hours before addition of MTT. MTT isprepared in phosphate buffered saline (Irvine Scientific #9240) at aconcentration of 2mg/mL. 50 μL per well of MTT solution is added to the200 μL of media to yield a final concentration of 0.4 mg/mL and platesare returned to the incubator for 4 hours. After 4 hours incubation themedia, compound and MTT mixture is aspirated from the plates and 100 μLof 100% DMSO is added to each well in addition to 25 μL of Sorenson'sBuffer (0.1M glycine, 0.1M NaCl, pH 10.5). Quantitation of metabolicreduction of MTT in each plate is performed by reading optical densityat 570 nm wavelength on a Molecular Devices UVmax microplate reader.Growth inhibition curves and 50% inhibitory concentrations aredetermined using Microsoft Excel.

Representative data are summarized in Table 4. Table 4 illustrates theinhibitory activity of compounds of the present invention against arepresentative kinase (raf) and the cytotoxicity of compounds of thepresent invention against a broad range of human tumor cell lines.

TABLE 4 MTT MTT MIA Paca MTT MTT MTT SW620 (pancre- MDA 468 PC- HT-29Example Raf (colon) atic) (breast) (prostate) (colon) 2 + ++ ++ ++ +++++ 133 + +++ +++ ++ +++ ++ 25 ++ +++ +++ +++ +++ +++ 1 + +++ +++ +++ ++++++ 119 + ++ ++ ++ ++ ++ 130 + +++ +++ +++ ++++ ++++ 8 + +++ +++ +++ ++++++ 121 + ++ +++ ++ ND ++ 117 +++ + ND + ND ++ 143 + ++ ND ++ ND ++ KeySymbol Range + <0.50 μM ++ 0.50-5 μM +++ 5-50 μM ++++ >50 μM ND no data

IN VIVO ASSAYS Anti-Tumor Studies: Animals

Mice are acquired from Taconic Farms and are maintained in Microisolatorcages at 72±2° F. with a 12 hour light/dark cycle. Animals are housed at4 mice per cage (28×17×12 cm ) and are given food and water ad libitum.Animals are numbered through the use of an ear punch or tail tattoo. Allanimal handling is done in a laminar flow hood.

Cell Growth

SW620, available from the American Type Culture Collection, are grown inmedia consisting of RPMI 1640 with fetal bovine serum (10%), sodiumpyruvate (1.0 mM) and glutamine (2.0 mM). Cells are incubated at 37° C.in 5% CO₂. Cells are harvested with trypsin (0.05%), centrifuged, andresuspended in PBS:matrigel (1:1) at 1×10⁷ cell/ml.

Tumor Implantation

One of the tumor cell lines used is the colon line SW620. Tumors areinitiated by subcutaneous injection of a cell suspension into the rightflank of each mouse. The inoculum consists of 2×10⁶ cells/mouse/ 0.2 mlin PBS:matrigel (1:1).

Tumor Measurement

Solid tumors are measured by caliper measurement through the skin.Caliper measurements are typically made twice weekly. Tumor weight iscalculated using the equation (length×width²/2)=mg tumor weight.

Body Weight Measurement

Mice are weighed twice weekly at the time of tumor measurement.

Compound Preparation

Compounds are prepared in a vehicle consisting of DMSO, Cremophore andPBS.

Experimental Therapy

Drug therapy begins when the average tumor size is approximately 40-50mg, which usually is day 7 after implant. The dose schedule consists ofone dose/day for 5 consecutive days. Drugs are administered at 3 or 4dose-levels based upon the previously-determined maximally tolerateddose. A vehicle control group is also included. Drugs may beadministered by either i.v., i.p., s.c., or oral (p.o.) transdermalroutes or other alternative routes. Drugs may be administered via tailvein infusion. The injection volume administered for each mouse isusually 0.01-0.02 mL/g of body weight. In the case of i.v. injectionsand tail vein infusion animals are restrained in a Broome restrainerduring handling. Animal are fasted overnight prior to p.o. dosing. Theduration of each experiment is typically 28 days from tumor implant.

Representative results are listed in Table 5.

TABLE 5 in vivo data Tumor Response Example Xenograft % Inhibition @mg/kg 2 HT-29 50% @ 5 mg/kg 85 SW620 40% @ 50 mg/kg 84 HT-29 50% @ 25mg/kg

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for cancerconditions, or for other indications for the compounds of the inventionindicated above. Likewise, the specific pharmacologic responses observedmay vary according to and depending upon the particular active compoundselected or whether there are present pharmaceutical carriers, as wellas the type of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

What is claimed is:
 1. A compound of formula (I)

wherein R¹ is H or is optionally joined with R² to form a fused ringselected from the group consisting of five to ten membered aryl,heteroaryl or heterocyclyl rings, said heteroaryl or said heterocyclylrings having one to three heteroatoms where zero to three of saidheteroatoms are N and zero to 1 of said heteroatoms are O or S and wheresaid fused ring is optionally substituted by one to three of R⁹, whereR² and R⁹ are as defined below; R² and R³ are independently H, HET,aryl, C₁₋₁₂ aliphatic, CN, NO₂, halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰,—SO₂R¹⁰, —NR¹⁰R¹¹, —NR¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹²,—NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹,—SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹ where said C₁₋₁₂ aliphaticoptionally bears one or two insertions of one to two groups selectedfrom C(O), O, S, S(O), SO₂ or NR¹²; with said HET, aryl or C₁₋₁₂aliphatic being optionally substituted by one to three of R¹⁰; and whereR² is optionally joined with R³ to form a fused ring selected from thegroup consisting of five to ten membered aryl, heteroaryl orheterocyclyl rings, said heteroaryl or said heterocyclyl rings havingzero to three heteroatoms where zero to three of said heteroatoms are Nand zero to one of said heteroatoms are O or S and where said fused ringis optionally substituted by one to three of R⁹; where HET, R⁹, R¹⁰, R¹¹and R¹² are as defined below; or R² and R³ are independently —R¹²NH₂,—R¹²-halogen, —COR¹¹NR¹²R¹¹, —C(NH)R¹¹, where R¹¹ is as defined below,and R¹² is H, C₁₋₆ aliphatic, NO₂, C₁₋₆ alkoxy, halogen, aryl or HET,said C₁₋₆ aliphatic optionally substituted by one to three of halogen orOH, where HET is as defined below; R⁴ is H, halogen, NO₂ or CN; R⁵ is Hor C₁₋₁₂ aliphatic optionally substituted by one to three of halo,hydroxyl, or aryl; R⁶ and R⁷ are independently bromo or chloro; R⁸ isOH; each R⁹is independently halogen, C₁₋₁₂ aliphatic, CN, —NO₂, R¹⁰,—OR¹¹, —SR¹¹, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —N¹¹R¹², —NR¹²COR¹¹,—NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —CO₂R¹¹,—CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹ or C(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹and R¹² are as defined below; each R¹⁰ is independently H, halogen,C₁₋₁₂ aliphatic, aryl or HET, where said C₁₋₁₂ aliphatic optionallybears an inserted one to two groups selected from O, S, S(O), SO₂ orNR¹², where said C₁₋₁₂ aliphatic, aryl or HET is optionally substitutedby one to three of halo, another HET, aryl, CN, —SR¹², —OR¹², —N(R²)₂,—S(O)R¹², —SO₂R¹², SO₂N(R¹²)₂, —NR¹²COR¹², —NR¹²CO₂R¹², —NR¹²CON(R¹²)₂,—NR¹²(NR¹²)NHR¹², —CO₂R¹², —CON(R¹²)₂, —NR¹²SO₂R¹², —OCON(R¹²)₂, whereHET and R¹² are as defined below; or each R¹⁰ is independently C₁₋₆aliphatic, aryl or HET optionally substituted by one to three of NO₂,R¹², —R¹²N(R¹²)₂ or trifluoro, where R¹² is H, C₁₋₆ aliphatic, NO₂, C₁₋₆alkoxy, halogen, aryl or HET, said C₁₋₆ aliphatic optionally substitutedby one to three of halogen or OH, where HET is as defined below; or eachR¹⁰ is oxo, cyano or amino; or each R⁹ is —COR¹⁰, where R¹⁰ is H, C₁₋₆aliphatic or amino; R¹¹ is H or R¹⁰; R¹² is H, C₁₋₁₂ aliphatic or HET,said C₁₋₁₂ aliphatic optionally substituted by one to three of halogenor OH where HET is as defined below; or R¹² is NO₂, C₁₋₆ alkoxy, halogenor aryl; HET is a five to ten-membered saturated or unsaturatedheterocyclic ring selected from the group consisting of benzofuran,benzoxazole, dioxin, dioxane, dioxolane, dithiane, dithiazine,dithiazole, dithiolane, furan, imidazole, indole, indazole, morpholine,oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxiadiazine,piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine,pyrrole, pyrrolidine, quinoline, quinazoline, tetrahydrofuran,tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole,thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran,triazine, and triazole; or R¹² is (R¹¹)₂N—C₁₋₆ aliphatic, where R¹¹ isH, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic, phenyl, phenyl-C, aliphaticor HET, where HET is oxazole, pyridine, tetrazole or thiazole; and andthe pharmaceutically acceptable salts or solvates thereof.
 2. A compoundof formula (I) as claimed in claim 1 wherein R² and R³ are independentlyH, HET, aryl, C₁₋₁₂ aliphatic, CN, NO₂, halogen, R¹⁰, —OR¹⁰, —SR¹⁰,—S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹, —NR¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹,—NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR¹¹, —COR¹¹, —CO₂R¹¹,—CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹ where said C₁₋₁₂aliphatic optionally bears one or two insertions of one to two groupsselected from C(O), O, S, S(O), SO₂ or NR¹²; with said HET, aryl orC₁₋₁₂ aliphatic being optionally substituted by one to three of R¹⁰; andwhere R² is optionally joined with R³ to form a fused ring selected fromthe group consisting of five to ten membered aryl, heteroaryl orheterocyclyl rings, said heteroaryl or said heterocyclyl rings havingzero to three heteroatoms where zero to three of said heteroatoms are Nand zero to one of said heteroatoms are O or S and where said fused ringis optionally substituted by one to three of R⁹; where HET, R⁹, R¹⁰, R¹¹and R¹² are as defined below; each R¹⁰ is independently H, halogen,C₁₋₁₂ aliphatic, aryl or HET, where said C₁₋₁₂ aliphatic optionallybears an inserted one to two groups selected from O, S, S(O), SO₂ orNR¹², where said C₁₋₁₂ aliphatic, aryl or HET is optionally substitutedby one to three of halo, another HET, aryl, CN, —SR¹², —OR¹², —N(R¹²)₂,—S(O)R¹², —SO₂R¹², —SO₂N(R¹²)₂, —NR¹²COR¹², —NR¹²CO₂R¹², —NR¹²CON(R¹²)₂,—NR¹²(NR¹²)NHR¹², —CO₂R¹², —CON(R¹²)₂, —NR¹²SO₂R¹², —OCON(R¹²)₂, whereHET and R¹² are as defined below; R¹² is H, C₁₋₁₂ aliphatic or HET, saidC₁₋₁₂ aliphatic optionally substituted by one to three of halogen or OHwhere HET is as defined below; and HET, R¹, R⁴, R⁵, R⁶, R⁷, R⁸ R⁹ andR¹¹ are as defined in claim 1; and the pharmaceutically acceptable saltsor solvates thereof.
 3. A compound of formula (I) as claimed in claim 2wherein R¹ is H or is optionally joined with R² to form a fused ringselected from the group as defined for HET below, and where said fusedring is optionally substituted by one to three of R⁹, where R² and R⁹are as defined below; R² and R³ are independently H, HET, aryl, C₁₋₆aliphatic, CN, NO₂, halogen, R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —SO₂R¹⁰,—NR¹⁰R¹¹, —NR¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹²,—NR¹²SO₂R¹¹, —NR¹²C(NR¹²)NHR^(11 , —COR) ¹¹, —CO₂R¹¹, —CONR¹²R¹¹,—SO₂NR¹²R¹¹, —OCONR¹²R¹¹, C(NR¹²)NR¹²R¹¹ where said C₁₋₆ aliphaticoptionally bears one or two insertions of one to two groups selectedfrom C(O), O, S, S(O), SO₂ or NR¹²; with said HET, aryl or C₁₋₆aliphatic being optionally substituted by one to three of R¹⁰; and whereR² is optionally joined with R³ to form a fused ring selected from thegroup as defined for HET below and where said fused ring is optionallysubstituted by one to three of R⁹, where HET, R⁹, R¹⁰, R¹¹ and R¹² areas defined below; R⁵ is H or C₁₋₆ aliphatic optionally substituted byone to three of halo, OH, or aryl; each R⁹ is independently halo, C₁₋₆aliphatic, CN, —NO₂, R¹⁰, —OR¹¹, —SR¹¹, —S(O)R¹⁰, —SO₂R¹⁰, —NR¹⁰R¹¹,—N¹¹R¹², —NR¹²COR¹¹, —NR¹²CO₂R¹¹, —NR¹²CONR¹¹R¹², —NR¹²SO₂R¹¹,—NR¹²C(NR¹²)NHR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, —OCONR¹²R¹¹ orC(NR¹²)NR¹²R¹¹, where R¹⁰, R¹¹ and R¹² are as defined below; each R¹⁰ isindependently H, halogen, C₁₋₆ aliphatic, aryl or HET, where said C₁₋₆aliphatic optionally bears an inserted one to two groups selected fromO, S, S(O), SO₂ or NR¹², where said C₁₋₆ aliphatic, aryl or HET isoptionally substituted by one to three of halo, another HET, aryl, CN,—SR¹², —OR¹², —N(R¹²)₂, —S(O)R¹², —SO₂R¹², —SO₂N(R¹²)₂, —NR¹²COR¹²,—NR¹²CO₂R¹², —NR¹²CON(R¹²)₂, —NR¹²(NR¹²)NHR¹², —CO₂R¹², —CON(R¹²)₂,—NR¹²SO₂R¹², —OCON(R¹²)₂, where HET and R¹² are as defined below; R¹² isH, C₁₋₆ aliphatic or HET, said C₁₋₆ aliphatic optionally substituted byone to three of halogen or OH where HET is as defined below; and HET,R⁴, R⁶, R⁷, R³ and R¹¹ are as defined in claim 1; and thepharmaceutically acceptable salts or solvates thereof.
 4. A compound offormula (I) as claimed in claim 1 wherein R¹ is H or is optionallyjoined with R² to form a fused ring selected from the group consistingof fused pyridine, fused triazole, fused thiazole or fusedamino-substituted thiazole; or R¹ and R² comprise a fused ring which ismethyl substituted fused pyridine. HET is a five or six-memberedsaturated or unsaturated heteroaryl ring selected from the groupconsisting of dioxin, dioxane dioxolane, dithiane, dithiazine,dithiazole, dithiolane, furan, imidazole, imidazopyridinyl, morpholine,oxazole, oxadiazoie, oxathiazole, oxathiazolidine, oxazine, oxiadiazine,piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine,pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiophene,thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole,thiomorpholine, thiopyran, thioxotriazine, triazine, and triazole; R²,R³, R¹⁰ and R¹² are as defined in claim 1; R⁴, R⁶, R⁷, R⁸ and R¹¹ are asdefined in claim 1; and R⁵ and R⁹ are as defined in claim 3; and thepharmaceutically acceptable salts or solvates thereof.
 5. A compound offormula (I) as claimed in claim 1 wherein R¹ is H or is optionallyjoined with R² to form a fused ring selected from the group consistingof five to six membered heteroaryl rings, said heteroaryl ring havingone to two heteroatoms where zero to two of said heteroatoms are N andzero to two of said heteroatoms are O or S and where said fused ring isoptionally substituted by one to three of R⁹, where R² and R⁹ are asdefined below; R² and R³ are independently H, HET, phenyl, C₁₋₆aliphatic, —NR¹⁰R¹¹, —COR¹¹, —CO₂R¹¹, —CONR¹²R¹¹, —SO₂NR¹²R¹¹, with saidHET, phenyl or C₁₋₆ aliphatic being optionally substituted by R¹⁰; andwhere R² is optionally joined with R³ to form a fused five memberedheterocyclyl ring, said heterocyclyl ring having zero to 1 heteroatomswhere said heteroatom is N and zero to 1 heteroatoms where saidheteroatoms are O or S and where said fused ring is optionallysubstituted by R⁹, where HET, R⁹, R¹⁰, R¹¹ and R¹² are as defined below;R⁴ is H; R⁵ is H; R⁶, R⁷ and R⁸ are as defined in claim 1; R⁹ is C₁₋₆aliphatic or —COR¹⁰, where R¹⁰ is as defined below; R¹⁰ is H, C₁₋₆aliphatic or amino; R¹¹ is H, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic,phenyl, phenyl-C₁₋₆ aliphatic or HET; R¹² is H, C₁₋₆ aliphatic,hydroxy-C₁₋₆ aliphatic or (R¹¹)₂N—C₁₋₆ aliphatic; and HET is aheterocyclic ring selected from the group consisting of oxazole,pyridine, tetrazole and thiazole; and the pharmaceutically acceptablesalts or solvates thereof.
 6. A compound of formula (I) as claimed inclaim 1 wherein R¹ is H; R² and R³ are independently H, HET, phenyl,C₁₋₆ aliphatic, cyano, halogen, —COR¹¹, or —CONR¹²R¹¹, with said HET,phenyl or C₁₋₆ aliphatic being optionally substituted by R¹⁰, where HET,R¹⁰, R¹¹ and R¹² are as defined below; R⁴ is H; R⁵ is H; R⁶, R⁷ and R⁸are as defined in claim 1; R¹⁰ is H, C₁₋₆ aliphatic, oxo or cyano; R¹¹is H, C₁₋₆ aliphatic, trihalo-C₁₋₆ aliphatic, phenyl ornitro-substituted phenyl; R¹² is H, C₁₋₆ aliphatic, hydroxy-C₁₋₆aliphatic; and HET is thiophene or pyridine; and the pharmaceuticallyacceptable salts or solvates thereof.
 7. A compound as claimed in claim1, selected from the group consisting of


8. A compound as claimed in claim 1, selected from the group consistingof:


9. A compound as claimed in claim 1, selected from the group consistingof:


10. A compound as claimed in claim 1, selected from the group consistingof:


11. The compound3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-pyrid-3-yl-1,3-dihydro-indol-2-one;and pharmaceutically acceptable salts and solates thereof.
 12. Acompound as claimed in claim 1, wherein said compound is in the Egeometric isomer form.
 13. A compound as claimed in claim 1, whereinsaid compound is in the Z geometric isomer form.
 14. A compound asclaimed in claim 1, wherein said compound is a mixture of the Zgeometric isomer form and the E geometric isomer form.
 15. A compound asclaimed in claim 1, having a chiral carbon atom and which compound isdextrorotatory.
 16. A compound as claimed in claim 1, having a chiralcarbon atom and which compound is levorotatory.
 17. A compound asclaimed in claim 1, having a chiral carbon atom and which is a mixtureof dextrorotatory and levorotatory.
 18. A prodrug of a compound asclaimed in claim 1 which is a biohydrolyzable ester, biohydrolyzableamide, biohydrolyzable carbamate, biohydrolyzable carbonate orbiohydrolyzable ureide, said biohydrolyzable functionality being linkedto the OH group representing R⁸ in the compound of formula (I).
 19. Aprodrug as claimed in claim 18 wherein said OH group is conjugated witha carbamoyl conjugate to yield a biohydrolyzable carbamate wherein saidcarbamoyl conjugate is selected from the group consisting ofdiethylaminocarbonyl, N-(2-hydroxyethyl)aminocarbonyl,N,N,-bis(2-hydroxyethyl)aminocarbonyl,hydroxyethyloxyethylaminocarbonyl, 4-morpholinocarbonyl and4-methyl-i-piperazinylcarbonyl.
 20. A prodrug as claimed in claim 19selected from


21. A prodrug as claimed in claim 18 wherein said OH group is conjugatedwith a carbonate conjugate to yield a biohydrolyzable carbonate whereinsaid carbonyl conjugate is selected from the group consisting ofphenylmethyloxycarbonyl, ethyloxycarbonyl, isobutyloxycarbonyl, andpyridinemethyloxycarbonyl.
 22. A prodrug as claimed in claim 18 whereinsaid OH group is conjugated with an ester conjugate to yield abiohydrolyzable ester wherein said ester conjugate ist-butylcarbonyloxymethyl.
 23. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a pharmacologically effectiveamount of a compound as claimed in claim
 1. 24. A process for thepreparation of a compound of formula (I) as claimed in claim 1, whichprocess comprises the reaction of a compound of formula (II)

wherein R⁵, R⁶, R⁷ and R⁸ are as defined in claim 1, with a compound offormula (III)

wherein R¹, R², R³ and R⁴ are as defined in claim
 1. 25. A method oftreating a disease mediated by cRaf1 kinase, said method comprising thestep of administering to a mammal in need thereof a pharmacologicallyeffective amount of a compound as claimed in claim
 1. 26. A method ofinhibiting tumor growth, comprising the step of administering to apatient in need thereof a pharmacologically effective amount of acompound as claimed in claim 1.